a LANGE medical book
Clinical Neurology sixth edition
MICHAEL J. AMINOFF, MD, DSc, FRCP Professor and Executive Vice-Chair Department of Neurology School of Medicine University of California, San Francisco
DAVID A. GREENBERG, MD, PhD Professor and Vice-President for Special Research Programs Buck Institute for Age Research Novato, California
ROGER P. SIMON, MD Robert Stone Dow Chair of Neurology Director of Neurobiology Research Legacy Health Systems Portland, Oregon
Lange Medical Books/McGraw-Hill Medical Publishing Division New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto
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Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Chapter 1: Disorders of Cognitive Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Chapter 2: Headache & Facial Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Chapter 3: Disorders of Equilibrium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Chapter 4: Disturbances of Vision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Chapter 5: Motor Deficits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 Chapter 6: Disorders of Somatic Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 Chapter 7: Movement Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Chapter 8: Seizures & Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Chapter 9: Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 Chapter 10: Coma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Chapter 11: Neurologic Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 A: The Neurologic Examination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 B: A Brief Examination of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370 C: Clinical Examination of Common Isolated Peripheral Nerve Disorders. . . . . . . . . . . . . . . . . . . 372 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 Frequently Used Neurologic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inside Front Cover
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Preface The warm and generous acceptance of earlier editions of this book and the advances that have occurred in the neurosciences in the last few years have prompted the preparation of this sixth edition of Clinical Neurology. We have again provided a problem-based approach to neurology based on our experience in teaching medical students and house staff, primarily in the clinics and wards of the hospitals and clinics of the University of California, San Francisco. The chapters are focused on clinical problems because that is the manner in which patients typically come to medical attention, but this is followed in each chapter by a description of specific diseases and syndromes. The cornerstone of neurologic diagnosis remains a careful history and neurologic examination, and these continue to be emphasized in this new edition. Nevertheless, technologic advances, especially in neuroimaging, have facilitated the evaluation of patients presenting with neurologic disorders, and the application of these and other investigative techniques is discussed in greater detail than in earlier editions. The sections on treatment have been updated and expanded to reflect advances in the field. In addition, we have attempted to incorporate the latest developments in molecular biology and genetics, especially when these are of clinical relevance in advancing
concepts concerning the pathogenesis or treatment of disease. With the last edition, Key Concepts were introduced at the beginning of each chapter. Certain major concepts were presented with numbered icons that then appeared later in the text to indicate where these specific points were discussed. We have retained this approach in this edition also, and hope that readers continue to find it useful. We are grateful to our families for giving us the time to see this new edition to fruition. We also thank those of our colleagues who gave us help and advice us as we updated the text, and especially Lydia Bayne, Chadwick Christine, Jim Corbett, Paul Garcia, Hubert Leonard, Catherine Lomen-Hoerth, and Norman So. The staff at McGraw-Hill has again been very helpful in seeing this book through the production process, and we greatly appreciate their unfailing assistance. Michael J. Aminoff David A. Greenberg Roger P. Simon February 2005
vii Copyright © 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
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Disorders of Cognitive Function
1
CONTENTS I. Approach to diagnosis, 3 History, 3 General physical examination, 4 Neurologic examinations, 6 Laboratory investigations, 10 II. Acute confusional states, 11 Drugs, 11 Ethanol intoxication, 11 Ethanol withdrawal, 11 Sedative drug intoxication, 13 Sedative drug withdrawal, 14 Opioids, 14 Anticholinergic drugs, 15 Phencyclidine, 15 Endocrine disturbances, 15 Hypothyroidism, 15 Hyperthyroidism, 15 Hypoglycemia, 15 Hyperglycemia, 16 Hypoadrenalism, 16 Hyperadrenalism, 17 Electrolyte disorders, 17 Hyponatremia, 17 Hypercalcemia, 17 Hypocalcemia, 17 Nutritional disorders, 18 Wernicke encephalopathy, 18 Vitamin B12 deficiency, 18 Organ system failure, 19 Hepatic encephalopathy, 19 Reye syndrome, 19
Uremia, 20 Pulmonary encephalopathy, 20 Organ transplantation, 20 Meningitis, encephalitis, & sepsis, 20 Bacterial meningitis, 20 Tuberculous meningitis, 24 Syphilitic meningitis, 25 Lyme disease, 26 Viral meningitis & encephalitis, 26 Herpes simplex virus (HSV) encephalitis, 29 Acquired immunodeficiency syndrome (AIDS), 31 Fungal meningitis, 32 Parasitic infections, 34 Leptomeningeal metastases, 38 Sepsis, 39 Vascular disorders, 39 Hypertensive encephalopathy, 39 Subarachnoid hemorrhage, 41 Vertebrobasilar ischemia, 41 Right (nondominant) hemispheric infarction, 41 Systemic lupus erythematosus, 41 Disseminated intravascular coagulation, 41 Thrombotic thrombocytopenic purpura, 42
Head trauma, 43 Concussion, 43 Intracranial hemorrhage, 43 Seizures, 43 Postictal state, 43 Complex partial seizures, 43 Psychiatric disorders, 43 III. Dementia, 44 Approach to diagnosis, 44 Differential diagnosis, 46 Cerebral disorders without extrapyramidal features, 46 Alzheimer disease, 46 Frontotemporal dementia, 51 Creutzfeldt-Jakob disease, 51 Normal-pressure hydrocephalus, 52 Cerebral disorders with extrapyramidal features, 55 Dementia with Lewy bodies, 55 Corticobasal ganglionic degeneration, 56 Huntington disease, 56 Progressive supranuclear palsy, 56 Systemic disorders, 56 Cancer, 56 Infection, 56 Metabolic disorders, 59 Organ failure, 60
(continued on next page)
1 Copyright © 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
2 / CHAPTER 1
(continued from previous page) Trauma, 61 Vascular disorders, 61 Pseudodementia, 62 IV. Amnestic syndromes, 62 Acute amnesia, 63 Head trauma, 63 Hypoxia or ischemia, 63
Bilateral posterior cerebral artery occlusion, 64 Transient global amnesia, 64 Alcoholic blackouts, 65 Wernicke encephalopathy, 65 Dissociative (psychogenic) amnesia, 65
Chronic amnesia, 65 Alcoholic Korsakoff amnestic syndrome, 65 Postencephalitic amnesia, 66 Brain tumor, 66 Paraneoplastic limbic encephalitis, 66
KEY CONCEPTS Disorders of consciousness include disorders in which the level of consciousness (arousal or wakefulness) is impaired, such as acute confusional states and coma, and those in which the level of consciousness is normal but the content of consciousness is altered, such as dementia and amnestic disorders.
Certain causes of acute confusional state must be identified urgently because they may lead rapidly to severe structural brain damage or death, and prompt treatment can prevent these complications: hypoglycemia, bacterial meningitis, subarachnoid hemorrhage, and traumatic intracranial hemorrhage.
An acute confusional state can be most readily distinguished from dementia by the time course of the impairment: acute confusional states are acute or subacute in onset, typically developing over hours to days, whereas dementia is a chronic disorder that evolves over months or years.
The most common causes of dementia are Alzheimer disease, dementia with Lewy bodies, and vascular dementia; reversible causes of dementia are rare, but are important to diagnose.
Consciousness is awareness of the internal or external world, and disorders of consciousness can affect either the level of consciousness or the content of consciousness.
Disturbances of the Level of Consciousness Abnormalities of the level of consciousness are characterized by impaired arousal or wakefulness, and they result from acute lesions of the ascending reticular activating system (Figure 1–1) or both cerebral hemispheres. The most severe degree of depressed consciousness is coma, in which the patient is unresponsive and unarousable. Less severe depression of consciousness results in an acute confusional state or delirium, in which the patient responds to at least some stimuli in a purposeful manner but is sleepy, disoriented, and inattentive. In some acute confusional states, agitation predominates or alternates with drowsiness, and may be accompanied by autonomic changes (fever, tachycardia, hypertension, sweating, pallor, or
flushing), hallucinations, and motor abnormalities (tremor, asterixis, or myoclonus).
Disturbances of the Content of Consciousness Many pathologic conditions can impair the content of consciousness without altering the level of consciousness. Examples include isolated disorders of language or memory due to focal brain lesions and widespread deterioration of mental function (dementia) from more diffuse, chronic pathologic processes. Dementia differs from acute confusional states in several respects (Table 1–1), and distinguishing between these two syndromes is the pivotal step in evaluating a patient with altered consciousness. The time course of the disorder—acute or subacute in acute confusional states and chronic in dementia—is the single most helpful differentiating feature. Confusional states, dementia, and circumscribed
DISORDERS OF COGNITIVE FUNCTION / 3 Cerebral hemisphere Thalamus
sional states are acute to subacute in onset, whereas dementias are chronic disorders. In an acute confusional state, the observations of others may be the only historical information available. When dementia is suspected, it is useful to have access to a relative or close acquaintance who can furnish details about the patient’s previous level of functioning; the time when dysfunction became evident; and the nature of any changes in personality, behavior, mood, intellect, judgment, memory, or facility with language. Associated problems such as gait disorders, incontinence, and headaches also should be explored.
Prior Medical History
Brainstem reticular activating system
Figure 1–1. Brainstem reticular activating system and its ascending projections to the thalamus and cerebral hemispheres.
memory disorders are discussed in this chapter. Coma is discussed in Chapter 10.
I. APPROACH TO DIAGNOSIS Evaluation of the patient with a suspected disorder of consciousness is aimed first at characterizing the nature of the disorder (eg, acute confusional state, coma, dementia, amnestic syndrome) and second at determining the cause. The approach used is outlined below.
HISTORY History of Present Illness The history should establish the time course of the disorder and provide clues to its nature and cause. Confu-
A. CARDIOVASCULAR SYSTEM A history of stroke, hypertension, vasculitis, or cardiac disease may suggest a vascular cause of a confusional state or multiinfarct dementia. B. DIABETES Cognitive disturbance in diabetic patients may result from a hyperosmolar nonketotic state or insulin-induced hypoglycemia. C. SEIZURE DISORDER A history of epilepsy suggests ongoing seizures, a postictal state, or head trauma in a confused patient. D. HEAD TRAUMA Recent head trauma suggests intracranial hemorrhage. Remote head trauma may produce amnestic syndrome or chronic subdural hematoma with dementia. E. ALCOHOLISM Alcoholism predisposes patients to acute confusional states from intoxication, withdrawal, postictal state, head trauma, hepatic encephalopathy, and Wernicke encephalopathy. Chronic memory disturbance in an alcoholic is likely due to Korsakoff syndrome. F. DRUG HISTORY A confusional state can result from overdose with insulin, sedative-hypnotics, opioids, antidepressants, antipsychotic agents, or hallucinogens, or from sedative
Table 1–1. Differences between acute confusional states and dementia. Acute Confusional State
Dementia
Level of consciousness
Impaired
Not impaired, except occasionally late in course
Course
Acute to subacute; fluctuating
Chronic; steadily progressive
Autonomic hyperactivity
Often present
Absent
Prognosis
Usually reversible
Usually irreversible
4 / CHAPTER 1 drug withdrawal. Elderly patients may be more sensitive to the cognitive side effects of drugs that are well tolerated by younger patients. G. PSYCHIATRIC HISTORY A history of psychiatric illness may suggest overdose with psychotherapeutic drugs such as benzodiazepines, antidepressants, or antipsychotic agents; a previously undiagnosed medical disorder capable of producing organic psychosis (hypothyroidism, vitamin B12 deficiency); or a functional disorder masquerading as an acute confusional state or dementia. H. OTHER Individuals who engage in unprotected sexual intercourse, intravenous drug users, recipients of contaminated blood or clotting factor transfusions, the sexual partners of all these persons, and infants of infected mothers are at particular risk for developing acquired immunodeficiency syndrome (AIDS).
Family History The family history can point to a heredodegenerative disorder, such as Huntington disease, as the cause of dementia.
GENERAL PHYSICAL EXAMINATION A general physical examination helps to classify the disorder as either an acute confusional state or dementia and may suggest a systemic disease as its cause (Tables 1–2 and 1–3).
Vital Signs & General Appearance Fever, tachycardia, hypertension, and sweating occur in many confusional states, but meningitis or sepsis must receive early consideration in the febrile patient. Hypertension should raise the possibility of hypertensive encephalopathy, intracranial hemorrhage, renal disease, or Cushing syndrome. Hypothermia occurs with expo-
Table 1–2. Clinical features helpful in the differential diagnosis of acute confusional states. Feature Headache Vital signs Fever
Hypothermia
Most Suggestive of Head trauma, meningitis, subarachnoid hemorrhage Infectious meningitis, anticholinergic intoxication, withdrawal from ethanol or sedative drugs, sepsis Intoxication with ethanol or sedative drugs, hepatic encephalopathy, hypoglycemia, hypothyroidism, sepsis
Hypertension
Anticholinergic intoxication,withdrawal from ethanol or sedative drugs,hypertensive encephalopathy,subarachnoid hemorrhage,sympathomimetic intoxication
Tachycardia
Anticholinergic intoxication, withdrawal from ethanol or sedative drugs, thyrotoxicosis, sepsis
Bradycardia
Hypothyroidism
Hyperventilation
Hepatic encephalopathy, hyperglycemia, sepsis
Hypoventilation
Intoxication with ethanol or sedative drugs, opioid intoxication, pulmonary encephalopathy
General examination Meningismus Meningitis, subarachnoid hemorrhage Skin rash
Meningococcal meningitis
Feature Tetany Cranial nerves Papilledema
Most Suggestive of Hypocalcemia Hypertensive encephalopathy, intracranial mass
Dilated pupils
Head trauma, anticholinergic intoxication, withdrawal from ethanol or sedative drugs, sympathomimetic intoxication
Constricted pupils
Opioid intoxication
Nystagmus/ ophthalmoplegia
Intoxication with ethanol, sedative drugs, or phencyclidine, vertebrobasilar ischemia,Wernicke encephalopathy
Motor Tremor
Withdrawal from ethanol or sedative drugs, sympathomimetic intoxication, thyrotoxicosis
Asterixis
Metabolic encephalopathy
Hemiparesis
Cerebral infarction, head trauma, hyperglycemia, hypoglycemia
Other Seizures
Ataxia
Withdrawal from ethanol or sedative drugs, head trauma, hyperglycemia, hypoglycemia Intoxication with ethanol or sedative drugs,Wernicke encephalopathy
DISORDERS OF COGNITIVE FUNCTION / 5 Table 1–3. Clinical features helpful in the differential diagnosis of dementia. Feature History Unprotected sexual intercourse, intravenous drug abuse, hemophilia, or blood transfusions
Most Suggestive of AIDS dementia complex
Family history
Huntington disease,Wilson disease
Headache
Brain tumor, chronic subdural hematoma
Vital signs Hypothermia
Hypothyroidism
Hypertension
Multiinfarct dementia
Hypotension
Hypothyroidism
Bradycardia
Hypothyroidism
General examination Meningismus
Acquired hepatocerebral degeneration
Kayser-Fleischer rings
Wilson disease
Ophthalmoplegia
Progressive supranuclear palsy
Pseudobulbar palsy
Multiinfarct dementia, progressive supranuclear palsy
Motor Tremor
Acquired hepatocerebral degeneration
Myoclonus
Creutzfeldt-Jakob disease, AIDS dementia complex
Rigidity
Dementia with Lewy bodies, corticobasal ganglionic degeneration, acquired hepatocerebral degeneration, Creutzfeldt-Jakob disease, progressive supranuclear palsy,Wilson disease
Chorea
Huntington disease,Wilson disease
Other Gait apraxia Polyneuropathy with hyporeflexia
sure to cold, ethanol or sedative drug intoxication, hypoglycemia, hepatic encephalopathy, Wernicke encephalopathy, hypothyroidism, or shock. In most dementias, the patient does not appear acutely ill unless a systemic disorder is also present.
Head & Neck
Jaundice suggests hepatic disease, and lemon-yellow coloration of the skin may occur in vitamin B12 deficiency. Coarse dry skin, dry brittle hair, and subcutaneous edema are characteristic of hypothyroidism. Petechiae are seen in meningococcemia, and petechiae or ecchymoses may reflect coagulopathy caused by liver disease, disseminated intravascular coagulation, or thrombotic thrombocytopenia purpura. Hot, dry skin is characteristic of intoxication with anticholinergic drugs. Cushing syndrome may be associated with acne. Hyperpigmentation of the skin may be evidence of Addison disease. Needle tracks associated with intravenous drug use suggest drug overdose, AIDS, or infective endocarditis.
Dementia with Lewy bodies, corticobasal ganglionic degeneration, acquired hepatocerebral degeneration, Wilson disease, AIDS dementia complex
Asterixis
Brain tumor, chronic subdural hematoma
Skin & Mucous Membranes
Most Suggestive of
Argyll Robertson Neurosyphilis pupils
Chronic meningitis
Jaundice
Cranial nerves Papilledema
Feature
Normal pressure hydrocephalus Neurosyphilis, vitamin B12 deficiency, AIDS dementia complex
Examination of the head may reveal signs of trauma, such as scalp lacerations or contusions, postauricular hematoma (Battle sign), periorbital hematoma (raccoon eyes), hemotympanum, or cerebrospinal fluid (CSF) otorrhea or rhinorrhea. Percussion of the skull over a subdural hematoma may cause pain. Meningeal signs, such as neck stiffness on passive flexion, thigh flexion upon flexion of the neck (Brudzinski sign), or resistance to passive extension of the knee with the hip flexed (Kernig sign), are seen in meningitis and subarachnoid hemorrhage.
Chest & Abdomen Cardiac murmurs may be associated with infective endocarditis and its neurologic sequelae. Abdominal examination may reveal a source of systemic infection or suggest liver disease. Rectal examination may provide evidence of gastrointestinal bleeding, which often precipitates hepatic encephalopathy.
6 / CHAPTER 1
NEUROLOGIC EXAMINATIONS Mental Status Examination Evaluation of mental status (Table 1–4) helps to classify a disorder as a confusional state, dementia, a circumscribed cognitive disturbance (aphasia, amnesia), or a psychiatric illness. The mental status examination is most useful if performed in a standardized fashion, and complex functions can be adequately evaluated only when the basic processes upon which they depend are preserved. Thus, memory, language, calculation, or abstraction cannot be assessed reliably in a patient who is poorly arousable or inattentive. The Minimental Status Examination (Table 1–5) is often used as a rapid bedside screening test for dementia. In performing the mental status examination, the level of consciousness and attention are evaluated first. If these are impaired, an acute confusional state exists, Table 1–4. Comprehensive mental status examination. Level of consciousness Attention and concentration Language and speech Comprehension Repetition Fluency Naming Reading Writing Calculation Speech Mood and behavior Content of thought Hallucinations Delusions Abstraction Judgment Memory Immediate recall Recent memory Remote memory Integrative sensory function Astereognosis Agraphesthesia Two-point discrimination Allesthesia Extinction Unilateral neglect and anosognosia Disorders of spatial thought Integrative motor function Apraxia
Table 1–5. Minimental status examination. Item
Points1
Orientation Time (1 point each for year, season, month, date, and day of the week)
5
Place (1 point each for state, county, city, building, and floor or room)
5
Registration Repeat names of three objects (1 point per object)
3
Attention and calculation Serial 7s or spell “world” backward (1 point per subtraction or letter)
5
Recall Recall names of three objects repeated previously (1 point per object)
3
Language Name pencil and watch (1 point each)
2
Repeat “no ifs, ands, or buts”
1
Follow three-step command (1 point per step)
3
Read and follow:“close your eyes”
1
Write a complete sentence
1
Construction Copy two intersecting pentagons
1
Total
30
1 A total score of <24 should generally lead to more detailed investigation of the possibility of dementia, although norms vary to some extent with age and education. Adapted from Greenberg DA: Dementia. In: Geriatrics. Lonergan ET (editor), Appleton & Lange,
and it may be difficult or impossible to conduct the remainder of the mental status examination. If the level of consciousness and attention are adequate, more complex cortical functions are examined next to determine whether there is global cortical dysfunction, which indicates dementia. A. LEVEL OF CONSCIOUSNESS The level of consciousness is described in terms of the patient’s apparent state of wakefulness and response to stimuli. Impairment of the level of consciousness should always be documented by a written description of the patient’s responses to specific stimuli rather than by the use of nonspecific and imprecise terms such as “lethargy,” “stupor,” or “semicoma.” 1. Normal—The patient with a normal level of consciousness appears awake and alert, with eyes open at rest. Unless there is deafness or a language disorder,
DISORDERS OF COGNITIVE FUNCTION / 7 verbal stimulation results in appropriate verbal responses. 2. Impaired—Mild impairment of consciousness may be manifested by sleepiness from which the patient is easily aroused when spoken to. As consciousness is further impaired, the intensity of stimulation required for arousal increases, the duration of arousal declines, and the responses elicited become less purposeful. B. ATTENTION Attention is the ability to focus on a particular sensory stimulus to the exclusion of others; concentration is sustained attention. These processes are grossly impaired in acute confusional states, usually less impaired in dementia, and unaffected by focal brain lesions. Attention can be tested by asking the patient to repeat a series of digits or to indicate when a given letter appears in a random series. A normal person can repeat five to seven digits correctly and identify a letter in a series without error. C. LANGUAGE AND SPEECH The essential elements of language are comprehension, repetition, fluency, naming, reading, and writing, all of which should be tested when a language disorder (aphasia) is suspected. Calculation disorders (acalculia) are probably closely related to aphasia. Speech, the motor activity that is the final step in the expression of lan-
guage, is mediated by the lower cranial nerves and their supranuclear connections. Dysarthria, a disorder of articulation, is sometimes difficult to distinguish from aphasia, but it always spares oral and written language comprehension and written expression. Aphasia may be a feature of diffuse cortical disease, as it is in certain dementias, but language impairment with otherwise normal cognitive function should suggest a focal lesion in the dominant hemisphere. A disorder of comprehension (receptive, or Wernicke, aphasia) commonly leads to a false impression of a confusional state or psychiatric disturbance. There are a variety of aphasic syndromes, each characterized by a particular pattern of language impairment; several have fairly precise pathoanatomic correlations. In addition to the most classic syndromes, described in Figure 1–2, variations are sometimes observed. For example, global aphasia refers to a syndrome that incorporates elements of both expressive and receptive aphasia; however, it does not imply that aphasia is complete, and some degree of comprehension and of fluency may be preserved. Transcortical aphasias are conditions in which Wernicke area, the arcuate fasciculus, and Broca area are themselves preserved, but their connections to other parts of the brain are interrupted. These disconnection syndromes may be distinguished clinically by the fact that, since the circuit comprising Wernicke area, the arcuate fasciculus, and Broca area is intact, repetition is preserved.
Arcuate fasciculus
Broca area Wernicke area Language Functions Preserved Pathologic Site Wernicke area Arcuate fasciculus Broca area
Type of Aphasia Receptive Conductive Expressive
Comprehension – + +
Figure 1–2. Anatomic basis and clinical features of aphasias.
Repetition – – –
Fluency + + –
8 / CHAPTER 1 D. MOOD AND BEHAVIOR Demented patients may be apathetic, inappropriately elated, or depressed, and their moods can fluctuate. If the examination is otherwise normal, early dementia easily can be confused with depression. Delirious patients are agitated, noisy, and easily provoked to anger. E. CONTENT OF THOUGHT Abnormalities of thought content can help to distinguish organic from psychiatric disease. Visual hallucinations are common in acute confusional states, whereas auditory hallucinations and fixed delusions are most common with psychiatric disorders. Impairment of abstraction may be revealed by the patient’s concrete (literal) interpretation of proverbs or inability to recognize conceptual differences and similarities. Judgment is commonly tested by asking what the patient would do in a hypothetic situation, such as finding a stamped, addressed letter on the sidewalk. F. MEMORY 1. Functional components of memory—Memory is the ability to register, store, and ultimately retrieve information. Storage and retrieval of memories can be impaired by either diffuse cortical disease or focal bilateral dysfunction of the medial temporal lobes or their connections. a. Registration—The ability to receive information through the various sensory modalities is largely a function of attention. b. Storage—The process whereby selected new information is learned, or memorized, may be mediated by limbic structures, including the hippocampus. Stored memories are reinforced by repetition and by emotional significance; they are thought to be diffusely distributed in association areas of the cerebral cortex. c. Retrieval—Retrieval is the ability to access previously learned information. 2. Amnesia—Memory disorder (amnesia) may be an isolated deficit or one feature of global cognitive dysfunction. In acute confusional states, attention is impaired, resulting in defective registration and an inability to learn new material. In dementia, attention is typically normal and problems with recent and—to a lesser extent—remote memory usually predominate. In psychogenic amnesia, subjective and emotionally charged memories are affected more than retention of objective facts and events; in organic amnesia, the reverse is true. Isolated loss of memory for personal identity (the inability to remember one’s own name) in an awake and alert patient is virtually pathognomonic of a psychogenic disorder. Additional terms sometimes used to denote aspects of acute-onset amnesia (eg, following head trauma) include retrograde amnesia, loss of memory for events immediately prior to the onset of the disorder, and an-
terograde or posttraumatic amnesia, impairment of memory in the period following the insult. 3. Testing of memory—Memory is assessed clinically by testing immediate recall, recent memory, and remote memory, which correspond roughly to registration, storage, and retrieval, respectively. a. Immediate recall—Tests of immediate recall are similar to tests of attention and include having the patient repeat a random series of numbers or other information that has not been learned previously. The ability to repeat implies that the material has been registered. Most normal adults can repeat a series of seven numbers forward and five backward without difficulty. b. Recent memory—Tests of recent memory assess the ability to learn new material. Typically, the patient is given three or four items to remember and asked to recall them 3 minutes later. Nonverbal tests, in which an object previously shown to the patient is selected from a group of objects, may be useful, especially for patients with expressive aphasia. Orientation to place and time, which requires newly learned information, is another important test of recent memory. c. Remote memory—The practical distinction between recent and remote memory is that only recent memory requires an ongoing ability to learn new information. Remote memory is tested by asking the patient to recall material that someone of comparable cultural and educational background can be assumed to know. Common examples are personal, historical, or geographic data, but the questions selected must be appropriate for the patient, and personal items must be verifiable. G. INTEGRATIVE SENSORY FUNCTION Sensory integration disorders from parietal lobe lesions are manifested by misperception of or inattention to sensory stimuli on the contralateral side of the body, when the primary sensory modalities are intact. Patients with parietal lesions may exhibit the following signs: 1. Astereognosis—The patient cannot identify, by touch, an object placed in the hand. 2. Agraphesthesia—The patient is unable to identify a number written on the hand. 3. Absence of two-point discrimination—This is an inability to differentiate between a single stimulus and two simultaneously applied adjacent, but separated, stimuli that can be distinguished by a normal person. 4. Allesthesia—This is misplaced localization of a tactile stimulus. 5. Extinction—A visual or tactile stimulus is perceived when applied alone to the side contralateral to the lesion but not when stimuli are applied bilaterally. 6. Unilateral neglect and anosognosia—Body image disorders caused by parietal lobe lesions take the form of unilateral neglect. The patient tends not to use
DISORDERS OF COGNITIVE FUNCTION / 9 the contralateral limbs, may deny that there is anything wrong with them (anosognosia), and may even fail to recognize them. 7. Disorders of spatial thought—These include constructional apraxia, right/left disorientation, and neglect of external space on the side opposite the affected parietal lobe. Tests for constructional apraxia include having the patient fill in the numbers on a clock face, copy geometric figures, or build figures with blocks. H. INTEGRATIVE MOTOR FUNCTION Apraxia is the inability to perform previously learned tasks, such as finger snapping or clapping the hands together, despite intact motor and sensory function. Unilateral apraxias are commonly caused by contralateral premotor frontal cortex lesions. Bilateral apraxias, such as gait apraxia, may be seen with bifrontal or diffuse cerebral lesions.
Gait & Station It is useful to observe the patient standing and walking early in the neurologic examination, since these activities may reveal additional neurologic abnormalities associated with disturbed cognitive function.
Cranial Nerves In patients with impaired cognitive function, abnormalities associated with cranial nerves may suggest the underlying cause. A. LESIONS OF THE EYES AND EARS 1. Papilledema suggests an intracranial mass, hypertensive encephalopathy, or other process that increases intracranial pressure. 2. In the confused patient, pupillary constriction suggests opiate ingestion; dilated pupils are characteristic of anticholinergic intoxication but may also be a manifestation of generalized sympathetic hyperactivity. Small, irregular pupils that react poorly to light—but better to accommodation—can be seen in neurosyphilis. 3. Sedative drugs and Wernicke encephalopathy produce nystagmus or ophthalmoplegia. Selective impairment of vertical gaze (especially downward) occurs early in progressive supranuclear palsy. B. PSEUDOBULBAR PALSY This syndrome is characterized by dysarthria, dysphagia, hyperactive jaw jerk and gag reflexes, and uncontrollable laughing or crying unrelated to emotional state (pseudobulbar affect). It results from bilateral interruption of the corticobulbar and corticospinal tracts. Dementing processes that produce this syndrome include progressive supranuclear palsy and multiinfarct dementia.
C. MULTIPLE CRANIAL NEUROPATHIES These can accompany infectious or noninfectious meningitis or AIDS dementia complex.
Motor Findings A. ACUTE CONFUSIONAL STATE In the acutely confused patient, a variety of motor abnormalities may suggest the cause. 1. Hemiparesis is most apt to be due to an intracranial structural lesion, although focal neurologic signs may be present in metabolic disorders such as hypoglycemia and nonketotic hyperglycemia. 2. Tremor is common in sedative drug or ethanol withdrawal and other states accompanied by autonomic hyperactivity. 3. Asterixis, a flapping tremor of the outstretched hands or feet, is seen in hepatic, renal, and pulmonary encephalopathy and in drug intoxication. 4. Myoclonus, which consists of rapid shocklike muscle contractions, can occur with uremia, cerebral hypoxia, or hyperosmolar nonketotic states. 5. Cerebellar signs such as broad-based ataxic gait and, often, dysmetria on heel-knee-shin maneuver accompany Wernicke encephalopathy and sedative drug intoxication. B. DEMENTIA Motor signs are useful in the differential diagnosis of dementia. 1. Chorea—Huntington disease, Wilson disease. 2. Tremor, rigidity, or bradykinesia—Wilson disease, acquired hepatocerebral degeneration. 3. Myoclonus—Creutzfeldt-Jakob disease, AIDS dementia complex. 4. Ataxia—Spinocerebellar degenerations, Wilson disease, paraneoplastic syndromes, Creutzfeldt-Jakob disease, AIDS dementia complex. 5. Paraparesis—Vitamin B12 deficiency, hydrocephalus, AIDS dementia complex.
Abnormalities of Sensation & Tendon Reflexes Dementias associated with prominent sensory abnormalities and loss of tendon reflexes include vitamin B12 deficiency, neurosyphilis, and AIDS dementia complex.
Primitive Reflexes A number of reflexes that are present in infancy and subsequently disappear may be released by frontal lobe dysfunction in later life. It is presumed that such release results from loss of cortical inhibition of these primitive reflexes (frontal release signs), which include palmar and plantar grasps as well as palmomental, suck, snout,
10 / CHAPTER 1 rooting, and glabellar reflexes. Although these responses are often seen in both acute confusional states and dementia, many can also occur in normal elderly adults. Their presence alone does not constitute evidence of cognitive dysfunction. 1. The palmar grasp reflex is elicited by stroking the skin of the patient’s palm with the examiner’s fingers. If the reflex is present, the patient’s fingers close around those of the examiner. The force of the patient’s grasp may increase when the examiner attempts to withdraw the fingers, and the patient may be unable to voluntarily release the grasp. 2. The plantar grasp reflex consists of flexion and adduction of the toes in response to stimulation of the sole of the foot. 3. The palmomental reflex is elicited by scratching along the length of the palm of the hand and results in
contraction of ipsilateral chin (mentalis) and perioral (orbicularis oris) muscles. 4. The suck reflex consists of involuntary sucking movements following the stimulation of the lips. 5. The snout reflex is elicited by gently tapping the lips and results in their protrusion. 6. In the rooting reflex, stimulation of the lips causes them to deviate toward the stimulus. 7. The glabellar reflex is elicited by repetitive tapping on the forehead. Normal subjects blink only in response to the first several taps; persistent blinking is an abnormal response (Myerson sign).
LABORATORY INVESTIGATIONS Laboratory studies are critical in diagnosing disorders of cognitive function. Useful investigations are listed in Ta-
Table 1–6. Laboratory studies in acute confusional states. Test Blood WBC
Most Useful in Diagnosis of
Test ECG
Meningitis, encephalitis, sepsis
PT and PTT
Hepatic encephalopathy
Arterial blood gas
Hepatic encephalopathy, pulmonary encephalopathy, uremia, sepsis
Cerebrospinal fluid WBC, RBC
Most Useful in Diagnosis of Anticholinergic intoxication, vascular disorders Meningitis, encephalitis, subarachnoid hemorrhage
Gram’s stain
Bacterial meningitis
Sodium
Hyponatremia
AFB stain
Tuberculous meningitis
Serum urea nitrogen and creatinine
Uremia
India ink stain
Cryptococcal meningitis
Cultures
Infectious meningitis
Glucose
Hyperglycemia, hypoglycemia
Cytology
Leptomeningeal metastases
Osmolality
Alcohol intoxication, hyperglycemia
Glutamine
Hepatic encephalopathy
Liver function tests, ammonia
Hepatic encephalopathy, Reye syndrome
VDRL
Syphilitic meningitis Cryptococcal meningitis
Thyroid function tests
Hyperthyroidism, hypothyroidism
Cryptococcal antigen
Calcium
Hypercalcemia, hypocalcemia
Polymerase chain reaction
Drug screen
Drug intoxications
Cultures
Meningitis, sepsis
Bacterial meningitis, tuberculous meningitis, syphilitic meningitis, Lyme disease, viral meningitis and encephalitis, AIDS, leptomeningeal metastases
FTA or MHA-TP
Syphilitic meningitis
CT brain scan or MRI
HIV antibody titer
AIDS and related disorders
Cerebral infarction, intracranial hemorrhage, head trauma, toxoplasmosis, herpes simplex encephalitis, subarachnoid hemorrhage
EEG
Complex partial seizures, herpes simplex encephalitis, nonconvulsive seizures
Urine, gastric aspirate Drug screen Drug intoxication Stool Guaiac
Hepatic encephalopathy
DISORDERS OF COGNITIVE FUNCTION / 11 bles 1–6 and 1–7; those most likely to establish or support a diagnosis in acute confusional states are complete blood count, arterial blood gases and pH, serum sodium, serum glucose, serum urea nitrogen and creatinine, liver function tests, drug screens, blood cultures, stool test for occult blood, lumbar puncture, brain computed tomography (CT) scan or magnetic resonance imaging (MRI), and electroencephalogram (EEG). Some of these studies can yield a specific diagnosis. Abnormal arterial blood gas or cerebrospinal fluid (CSF) profiles, for example, narrow the differential diagnosis to one or a few possibilities (Tables 1–8 and 1–9). Reversible dementia may be diagnosed on the basis of laboratory studies (see Table 1–7). The most common reversible dementias are those due to intracranial masses, normal pressure hydrocephalus, thyroid dysfunction, and vitamin B12 deficiency.
II. ACUTE CONFUSIONAL STATES Common causes of acute confusional states are listed in Table 1–10. Table 1–7. Laboratory studies in dementia. Test Blood Hematocrit, mean corpuscular volume (MCV), peripheral blood smear, vitamin B12 level
Vitamin B12 deficiency
Liver function tests
Acquired hepatocerebral degeneration,Wilson disease
Ceruloplasmin, copper
Wilson disease
FTA or MHA-TP
Neurosyphilis
HIV antibody titer
AIDS dementia complex
CT scan or MRI
EEG
Differential Diagnosis
Metabolic acidosis (with increased anion gap)
Diabetic ketoacidosis, lactic acidosis (postictal, shock, sepsis), toxins (methanol, ethylene glycol, salicylates,1 paraldehyde), uremia
Respiratory alkalosis
Hepatic encephalopathy, pulmonary insufficiency, salicylates,1 sepsis
Respiratory acidosis
Pulmonary insufficiency, sedative drug overdose
1
Sepsis and salicylates produce a combined acid-base disorder.
DRUGS Many drugs can cause acute confusional states, especially when taken in greater than customary doses, in combination with other drugs, by patients with altered drug metabolism from hepatic or renal failure, by the elderly, or in the setting of preexisting cognitive impairment. A partial list of drugs that can produce acute confusional states is provided in Table 1–11.
ETHANOL INTOXICATION
Hypothyroidism
Cytology
Pattern
Most Useful in Diagnosis of
Thyroid function tests
Cerebrospinal fluid VDRL
Table 1–8. Arterial blood gases in acute confusional states.
Neurosyphilis Leptomeningeal metastases Brain tumor, chronic subdural hematoma, multiinfarct dementia, normal pressure hydrocephalus Creutzfeldt-Jakob disease
Ethanol intoxication produces a confusional state with nystagmus, dysarthria, and limb and gait ataxia. In nonalcoholics, signs correlate roughly with blood ethanol levels, but chronic alcoholics, who have developed tolerance to ethanol, may have very high levels without appearing intoxicated. Laboratory studies useful in confirming the diagnosis include blood alcohol levels and serum osmolality. In alcohol intoxication, serum osmolality determined by direct measurement exceeds the calculated osmolality (2 × serum sodium + 1⁄20 serum glucose + 1⁄3 serum urea nitrogen) by 22 mosm/L for every 100 mg/dL of ethanol present. Intoxicated patients are at high risk for head trauma. Alcohol ingestion may cause life-threatening hypoglycemia, and chronic alcoholism increases the risk of bacterial meningitis. Treatment is not required unless a withdrawal syndrome ensues, but alcoholic patients should receive thiamine to prevent Wernicke encephalopathy (see below).
ETHANOL WITHDRAWAL Three common withdrawal syndromes are recognized (Figure 1–3). Because of the associated risk of Wernicke encephalopathy (discussed later), patients presenting
12 / CHAPTER 1 Table 1–9. Cerebrospinal fluid profiles in acute confusional states. Opening Red Blood Appearance Pressure Cells
White Blood Cells
Glucose
Protein
Glutamine Smears −
Cultures
Normal
Clear, colorless
70–200 mm H2O
0/µL
≤5 mono- ≥45 nuclear/ mg/dL µL
≤451 mg/dL
<25 µg/dL
−
Bacterial meningitis
Cloudy
↑
Normal
↑↑ (PMN)2
↓↓
↑↑
Normal
Gram stain +
+
Tuberculous meningitis
Normal or cloudy
↑
Normal
↑ (MN)3,5
↓
↑
Normal
AFB stain +
±
Fungal meningitis
Normal or cloudy
Normal or ↑
Normal
↑ (MN)
↓
↑
Normal
India ink prep + (Cryptococcus)
±
Viral meningitis/ encephalitis
Normal
Normal or ↑
Normal4
↑ (MN)5
Normal6
Normal or ↑
Normal
−
±
Parasitic meningitis/ encephalitis
Normal or cloudy
Normal or ↑
Normal
↑ (MN,E)7 Normal
Normal or ↑
Normal
Amebas may be seen on wet mount
±
Leptomeningeal metastases
Normal or cloudy
Normal or ↑
Normal
Normal ↓↓ or ↑ (MN)
Normal or ↑
Normal
Cytology +
−
Subarachnoid hemorrhage
Pink-red (supernatant yellow)
↑
↑
Normal or ↑ (PMN)8
Normal or ↑8
↑
Normal
−
−
Hepatic encephalopathy
Normal
Normal
Normal
Normal
Normal
Normal
↑
−
−
1
Lumbar cerebrospinal fluid. PMN, polymorphonuclear predominance. 3 MN, mononuclear (lymphocytic or monocytic) predominance. 4 Red blood cell count may be elevated in herpes simplex encephalitis. 5 PMN predominance may be seen early in course. 6 Glucose may be decreased in herpes or mumps infections. 7 E, eosinophils often present. 8 Pleocytosis and low glucose, sometimes seen several days after hemorrhage, reflect chemical meningitis caused by subarachnoid blood. +, positive; −, negative; ±, can be positive or negative. 2
with these syndromes should be given thiamine, 100 mg/d, intravenously or intramuscularly, until a normal diet can be ensured. 1. TREMULOUSNESS & HALLUCINATIONS This self-limited condition occurs within 2 days after cessation of drinking and is characterized by tremulous-
ness, agitation, anorexia, nausea, insomnia, tachycardia, and hypertension. Confusion, if present, is mild. Illusions and hallucinations, usually visual, occur in about 25% of patients. Treatment with diazepam, 5–20 mg, or chlordiazepoxide, 25–50 mg, orally every 4 hours, will terminate the syndrome and prevent more serious consequences of withdrawal.
DISORDERS OF COGNITIVE FUNCTION / 13 Table 1–10. Common causes of acute confusional states. Metabolic Disorders Drugs1 Ethanol intoxication Ethanol withdrawal Sedative drug intoxication Sedative drug withdrawal Opioids Anticholinergics Phencyclidine Endocrine disorders Hypothyroidism Hyperthyroidism Hypoglycemia Hyperglycemia Electrolyte disorders Hyponatremia Hypocalcemia Hypercalcemia Nutritional disorders Wernicke encephalopathy Vitamin B12 deficiency Organ system failure Hepatic encephalopathy Reye syndrome Uremia Dialysis disequilibrium Pulmonary encephalopathy Organ transplantation 1
Infectious and Noninfectious Meningitis/Encephalitis Bacterial meningitis Tuberculous meningitis Syphilitic meningitis Viral meningoencephalitis Herpes simplex virus encephalitis AIDS Fungal meningitis Parasitic infections Leptomeningeal metastases Vascular Disorders Hypertensive encephalopathy Subarachnoid hemorrhage Vertebrobasilar ischemia Right (nondominant) hemisphere infarction Systemic lupus erythematosus Disseminated intravascular coagulation Thrombotic thrombocytopenic purpura Head Trauma Concussion Intracranial hemorrhage Seizures Postictal state Complex partial seizure
See also Table 1–11.
2. SEIZURES Ethanol withdrawal seizures occur within 48 hours of abstinence, and within 7–24 hours in about two-thirds of cases. Roughly 40% of patients who experience seizures have a single seizure; more than 90% have between one and six seizures. In 85% of the cases, the interval between the first and last seizures is 6 hours or less. Anticonvulsants are usually not required, as seizures cease spontaneously in most cases. Unusual features such as focal seizures, prolonged duration of seizures (>6–12 hours), more than six seizures, status epilepticus, or a prolonged postictal state should prompt a search for other causes or complicating factors, such as head trauma or infection. The patient should be observed for 6–12 hours to make certain that atypical features are not present. Because patients with withdrawal seizures may develop delirium tremens, diazepam or chlordiazepoxide is sometimes given prophylactically. 3. DELIRIUM TREMENS This most serious ethanol withdrawal syndrome typically begins 3–5 days after cessation of drinking and
lasts for up to 72 hours. It is characterized by confusion, agitation, fever, sweating, tachycardia, hypertension, and hallucinations. Death may result from concomitant infection, pancreatitis, cardiovascular collapse, or trauma. Treatment consists of diazepam, 10–20 mg intravenously, repeated every 5 minutes as needed until the patient is calm, and correction of fluid and electrolyte abnormalities and hypoglycemia. The total requirement for diazepam may exceed 100 mg/h. Concomitant β-adrenergic receptor blockade with atenolol, 50–100 mg/d, also has been recommended.
SEDATIVE DRUG INTOXICATION The classic signs of sedative drug overdose are confusional state or coma, respiratory depression, hypotension, hypothermia, reactive pupils, nystagmus or absence of ocular movements, ataxia, dysarthria, and hyporeflexia. The most commonly used sedative-hypnotic drugs are benzodiazepines and barbiturates. Glutethimide or very high doses of barbiturates may produce large, fixed pupils. Decerebrate and decorticate posturing can occur in coma that is caused by sedative
14 / CHAPTER 1 Table 1–11. Some therapeutic drugs associated with acute confusional states. Acyclovir Amantadine Aminocaproic acid Amphetamines Anticholinergics Anticonvulsants Antidepressants Antihistamines (H1 and H2) Antipsychotics L-Asparaginase Baclofen Barbiturates Benzodiazepines β-Adrenergic receptor antagonists Cephalosporins Chloroquine Clonidine Cocaine Corticosteroids Cycloserine Cyclosporine Digitalis glycosides
Disulfiram Ergot alkaloids Ethanol Ganciclovir Hallucinogens Isoniazid Ketamine Levodopa Lidocaine Methylphenidate Methylxanthines Nonsteroidal antiinflammatory drugs Opioids Penicillin Phenylpropanolamine Quinacrine Quinidine Quinine Salicylates Selegiline Thyroid hormones
Percentage onset in each group
drug overdose. The diagnosis can be confirmed by toxicologic analysis of blood, urine, or gastric aspirate, but blood levels of short-acting sedatives do not correlate with clinical severity. Management is directed at supporting the patient’s respiratory and circulatory function while the drug is being cleared. Complications include aspiration pneu-
60
Tremulousness and hallucinations
50
Seizures
40 30
SEDATIVE DRUG WITHDRAWAL Clinical Findings Like ethanol, sedative drugs can produce confusional states or seizures when intake is stopped abruptly. The frequency and severity of withdrawal syndromes depend upon the duration of drug intake and the dose and half-life of the drug. They occur most often in patients taking large doses for at least several weeks. Intermediate- or short-acting agents are those most likely to produce withdrawal symptoms when discontinued. Withdrawal syndromes commonly develop 1–3 days after cessation of short-acting agents but may not appear until a week or more after longer-acting drugs are discontinued. Symptoms are identical to those of ethanol withdrawal and are similarly self-limited. Myoclonus and seizures may appear after 3–8 days, however, and may require treatment. Seizures usually occur only when the average daily drug intake is several times the usual therapeutic dose. A syndrome indistinguishable from delirium tremens may also occur, and also tends to be restricted to patients taking several times the drug’s daily sedative dose. Sedative drug withdrawal syndrome can be confirmed by evaluating the patient about 1 hour after administering pentobarbital, 200 mg orally or intramuscularly. The absence of signs of sedative drug intoxication (sedation, nystagmus, dysarthria, or ataxia) establishes that the patient is tolerant to sedative drugs and makes sedative drug withdrawal a likely diagnosis, although other causes must be excluded. Sedative drug withdrawal is treated with a long-acting barbiturate such as phenobarbital, administered orally to maintain a calm state without signs of intoxication, and tapered over about 2 weeks.
Delirium tremens
OPIOIDS
20 10 0
monia and pulmonary edema caused by fluid overload. Barring the development of infections or cardiovascular complications, patients who arrive at the hospital with adequate cardiopulmonary function should survive without sequelae.
0
1
2
3
4
5
6
7
14
Days after cessation of drinking
Figure 1–3. Ethanol withdrawal syndromes in relation to the time since cessation of drinking. (Data from Victor M, Adams RD: The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 1952;32:526–573.)
Opioids can produce analgesia, mood changes, confusional states, coma, respiratory depression, pulmonary edema, nausea and vomiting, pupillary constriction, hypotension, urinary retention, and reduced gastrointestinal motility. Their chronic use is associated with tolerance and physical dependence. Examination may reveal needle tracks or the abovementioned signs, but the cardinal features of opioid overdose are pinpoint pupils—which usually constrict in bright light—and respiratory depression. These features can also result from pontine hemorrhage, but opi-
DISORDERS OF COGNITIVE FUNCTION / 15 oid overdose can be distinguished by the patient’s response to the opioid antagonist naloxone. After administration of naloxone, pupillary dilation and full recovery of consciousness occur promptly. When large doses of opioids or multiple drug ingestions are involved, however, slight dilation of the pupils may be the only observable effect. Treatment involves intravenous administration of naloxone, 0.4–0.8 mg, and sometimes ventilatory support. Because naloxone’s action may be as short as 1 hour—and many opioids are longer-acting—it should be readministered as the patient’s condition dictates. With appropriate treatment, patients should recover uneventfully.
ANTICHOLINERGIC DRUGS Muscarinic anticholinergic drugs are used to treat gastrointestinal disturbances, parkinsonism, motion sickness, and insomnia. Antipsychotic drugs, tricyclic antidepressants, and many antihistamines also exhibit prominent anticholinergic activity. Overdose with any of these agents can produce a confusional state with agitation, hallucinations, fixed and dilated pupils, blurred vision, dry skin and mucous membranes, flushing, fever, urinary retention, and tachycardia. In some cases, the diagnosis can be confirmed by toxicologic analysis of blood or urine. Symptoms usually resolve spontaneously, but treatment may be required, especially if life-threatening cardiac arrhythmias occur. In such cases, the cholinesterase inhibitor physostigmine can reverse the abnormality by interfering with the breakdown of acetylcholine. However, physostigmine may produce bradycardia and seizures, so it is rarely used.
PHENCYCLIDINE Phencyclidine (PCP) can produce drowsiness, agitation, disorientation, amnesia, hallucinations, paranoia, and violent behavior. Neurologic examination may show large or small pupils, horizontal and vertical nystagmus, ataxia, hypertonicity, hyperreflexia, and myoclonus. There may be analgesia to a surprising degree. In severe cases, complications include hypertension, malignant hyperthermia, status epilepticus, coma, and death. Benzodiazepines may be useful for sedation and treating muscle spasms, and antihypertensives, anticonvulsants, and dantrolene (for malignant hyperthermia) may be required. Symptoms and signs usually resolve within 24 hours.
ENDOCRINE DISTURBANCES HYPOTHYROIDISM Profound hypothyroidism (myxedema) may produce a confusional state, coma, or dementia. Cognitive distur-
bances include flat affect, psychomotor retardation, agitation, and psychosis. The neurologic examination may show dysarthria, deafness, or ataxia, but the most characteristic abnormality is delayed relaxation of the tendon reflexes. Untreated, the condition can progress to seizures and coma. Laboratory abnormalities include low thyroid hormone [triiodothyronine(T3) and tetraiodothyronine (T4)] levels and elevated thyroid-stimulating hormone (TSH) and serum cholesterol. Hypoglycemia and hyponatremia may occur, and arterial blood gases may reveal respiratory acidosis. CSF protein is typically elevated; CSF pressure is occasionally increased. Treatment is of the underlying thyroid disorder and, in severe myxedema madness or coma, rapid thyroid replacement with levothyroxine together with hydrocortisone for the possible coexistent adrenal insufficiency.
HYPERTHYROIDISM Acute exacerbation of hyperthyroidism (thyrotoxic crisis) may cause a confusional state, coma, or death. In younger patients, agitation, hallucinations, and psychosis are common (activated crisis), whereas those over age 50 tend to be apathetic and depressed (apathetic crisis). Seizures may occur. Neurologic examination shows an exaggerated physiologic (action) tremor and hyperreflexia; ankle clonus and extensor plantar responses are rare. The diagnosis is confirmed by assaying thyroid hormones (T3 and T4) in the blood. Treatment includes correction of hyperthermia, fluid and electrolyte disorders, cardiac arrhythmias, and congestive heart failure, and administration of antithyroid drugs (propylthiouracil or methimazole), iodide, propranolol, and hydrocortisone. The underlying disorder that precipitated thyrotoxic crisis should also be sought.
HYPOGLYCEMIA Prompt treatment of hypoglycemia is essential because hypoglycemic encephalopathy may progress rapidly from a reversible to an irreversible stage, and definitive therapy can be quickly and easily administered. The most common cause is insulin overdose in diabetic patients, but oral hypoglycemic drugs, alcoholism, malnutrition, hepatic failure, insulinoma, and non-insulin-secreting fibromas, sarcomas, or fibrosarcomas may also be responsible. Neurologic symptoms usually develop over minutes to hours. Although no strict correlation between blood glucose levels and the severity of neurologic dysfunction can be demonstrated, prolonged hypoglycemia at levels of 30 mg/dL or lower invariably leads to irreversible brain damage.
16 / CHAPTER 1
Clinical Findings Early signs of hypoglycemia include tachycardia, sweating, and pupillary dilation, which may be followed by a confusional state with somnolence or agitation. Neurologic dysfunction progresses in a rostral-caudal fashion (see Chapter 10), and may mimic a mass lesion causing transtentorial herniation. Coma ensues, with spasticity, extensor plantar responses, and decorticate or decerebrate posturing. Signs of brain stem dysfunction subsequently appear, including abnormal ocular movements and loss of pupillary reflexes. Respiratory depression, bradycardia, hypotonia, and hyporeflexia ultimately supervene, at which point irreversible brain damage is imminent. Hypoglycemic coma is often associated with focal neurologic signs and focal or generalized seizures.
Table 1–12. Features of hyperglycemic encephalopathies. Diabetic Ketoacidosis
Hyperosmolar Nonketotic State
Patient age
Young
Middle-aged to elderly
Type of diabetes
Juvenile-onset or insulindependent
Adult-onset
Blood glucose (mg/dL)
300–600
>800
Serum osmolality (mosm/L)
<350
>350
Treatment
Ketosis
+
−
The diagnosis is confirmed by measuring blood glucose levels, but treatment with glucose—50 mL of 50% dextrose intravenously—should be begun immediately, before the blood glucose level is known. Improvement in the level of consciousness is evident within minutes after glucose administration in patients with reversible hypoglycemic encephalopathy. The consequences of inadvertently worsening what later proves to be hyperglycemic encephalopathy are never as serious as those of a failure to treat hypoglycemia.
Metabolic acidosis
+
−
Coma
Uncommon
Common
Focal neurologic signs
−
+
Seizures
−
+
HYPERGLYCEMIA
Treatment & Prognosis
Two hyperglycemic syndromes, diabetic ketoacidosis and hyperosmolar nonketotic hyperglycemia, can produce encephalopathy or coma. Either syndrome, distinguished by a variety of clinical and laboratory features (Table 1–12), may be the presenting manifestation of diabetes. Impaired cerebral metabolism, intravascular coagulation from hyperviscosity, and brain edema from rapid correction of hyperglycemia contribute to pathogenesis. Whereas the severity of hyperosmolarity correlates well with depression of consciousness, the degree of systemic acidosis does not.
Treatment of diabetic ketoacidosis includes insulin, fluid and electrolyte (especially potassium and phosphate) replacement, and antibiotics for concomitant infections. Blood glucose levels should be allowed to remain at 200–300 mg/dL for 24 hours to reduce the risk of brain edema. Deaths are usually related to sepsis, cardiovascular or cerebrovascular complications, or renal failure. In hyperosmolar nonketotic hyperglycemia, fluid replacement is most important; 0.5 N saline is administered except to patients with circulatory collapse, who should receive normal saline. Insulin is also required. Death is usually due to misdiagnosis or coexisting disease.
Clinical Findings Symptoms include blurred vision, dry skin, anorexia, polyuria, and polydipsia. Physical examination may show hypotension and other signs of dehydration, especially in hyperosmolar nonketotic hyperglycemia. Deep, rapid (Kussmaul) respiration characterizes diabetic ketoacidosis. Impairment of consciousness varies from mild confusion to coma. Focal neurologic signs and generalized or focal seizures are common in hyperosmolar nonketotic hyperglycemia. Laboratory findings are summarized in Table 1–12.
+, present; −, absent.
HYPOADRENALISM Adrenocortical insufficiency produces fatigue, weakness, weight loss, anorexia, hyperpigmentation of the skin, hypotension, nausea and vomiting, abdominal pain, and diarrhea or constipation. Neurologic manifestations include confusional states, seizures, or coma. Treatment is administration of hydrocortisone and correction of hypovolemia, hypoglycemia, electrolyte disturbances, and precipitating illnesses.
DISORDERS OF COGNITIVE FUNCTION / 17
HYPERADRENALISM Hyperadrenalism (Cushing syndrome) usually results from the administration of exogenous glucocorticoids. Clinical features include truncal obesity, facial flushing, hirsutism, menstrual irregularities, hypertension, weakness, cutaneous striae, acne, and ecchymoses. Neuropsychiatric disturbances are common and include depression or euphoria, anxiety, irritability, memory impairment, psychosis, delusions, and hallucinations; fully developed acute confusional states are rare. The diagnosis is confirmed by elevated 24-hour urine-free cortisol level or a defective response to a low-dose dexamethasone suppression test. When a pituitary tumor is the cause, the usual treatment is transsphenoidal hypophysectomy.
includes water restriction or, for severe symptoms, infusion of hypertonic saline with or without intravenous furosemide. Excessively rapid correction of hyponatremia may cause central pontine myelinolysis, a disorder of white matter that can produce a confusional state, paraparesis or quadriparesis, dysarthria, dysphagia, hyper- or hyporeflexia, and extensor plantar responses. Severe cases can result in the locked-in syndrome (see Chapter 10), coma, or death. MRI may show pontine and extrapontine white matter lesions. There is no treatment, so prevention is essential, and may best be achieved by restricting water intake and using small amounts of hypertonic saline to raise the serum sodium concentration to 125–130 mmol/L, at a rate not exceeding 8 mmol/L/d.
ELECTROLYTE DISORDERS
HYPERCALCEMIA
HYPONATREMIA Clinical Findings
Symptoms include thirst, polyuria, constipation, nausea and vomiting, abdominal pain, anorexia, and flank pain from nephrolithiasis. Neurologic symptoms are always present with serum calcium levels higher than 17 mg/dL (8.5 meq/L) and include headache, weakness, and lethargy. Physical examination may show dehydration, abdominal distention, focal neurologic signs, myopathic weakness, and a confusional state that can progress to coma. Seizures are rare. The myopathy spares bulbar muscles and tendon reflexes are usually normal. The diagnosis is confirmed by an elevated serum calcium level, and sometimes increased parathyroid hormone levels and a shortened QT interval on the ECG. Severe hypercalcemia is treated initially by vigorous intravenous hydration with 0.45% or 0.9% saline and usually requires central venous pressure monitoring. Patients with hypercalcemia also should be evaluated for occult cancer.
Hyponatremia, particularly when acute, causes brain swelling due to hypoosmolality of extracellular fluid. Symptoms include headache, lethargy, confusion, weakness, muscle cramps, nausea, and vomiting. Neurologic signs include confusional state or coma, papilledema, tremor, asterixis, rigidity, extensor plantar responses, and focal or generalized seizures. Hyponatremia may also produce focal signs by unmasking preexisting structural brain lesions. Neurologic complications are usually associated with serum sodium levels less than 120 meq/L (Figure 1–4), but may be seen following a rapid fall to 130 meq/L—while chronic hyponatremia with levels as low as 110 meq/L may be asymptomatic.
Treatment Treatment is most effective when the underlying cause of hyponatremia is corrected. Immediate management
Plasma Na+ (meq/L)
Alert
Confused Stupor
Coma Seizures
130 120 110 100 90
Figure 1–4. Relationship between plasma sodium concentration and neurologic manifestations of hyponatremia. (Reproduced, with permission, from Arieff AI, Llach F, Massry SG: Neurologic manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes. Medicine
HYPOCALCEMIA Symptoms include irritability, delirium, psychosis with hallucinations, depression, nausea, vomiting, abdominal pain, and paresthesias of the circumoral region and distal extremities. The most characteristic physical signs are those of overt or latent tetany. Neural hyperexcitability is exhibited by contraction of facial muscles in response to percussion of the facial (VII) nerve anterior to the ear (Chvostek sign). Carpopedal spasm may occur spontaneously or following tourniquet-induced limb ischemia (Trousseau sign). Cataracts and papilledema are sometimes present, and chorea has been reported. Seizures or laryngospasm can be life-threatening. Serum calcium levels are below 9 mg/dL (4.5 meq/L), but calcium is also decreased in hypoalbuminemia without affecting ionized calcium and hypocalcemia with normal ionized calcium is asympto-
18 / CHAPTER 1 matic. The ECG may show a prolonged QT interval. Treatment is with intravenous calcium gluconate and seizures, if present, are treated with phenytoin or phenobarbital.
within 1 month. Horizontal nystagmus and ataxia, however, resolve completely in only about 40% of cases. The major long-term complication of Wernicke encephalopathy is Korsakoff syndrome.
NUTRITIONAL DISORDERS
VITAMIN B12 DEFICIENCY
WERNICKE ENCEPHALOPATHY Wernicke encephalopathy is usually a complication of chronic alcoholism, but also occurs in other disorders associated with malnutrition. It is caused by deficiency of thiamine (vitamin B1). Pathologic features include neuronal loss, demyelination, and gliosis in periventricular gray matter. Proliferation of small blood vessels and petechial hemorrhages may be seen. The areas most commonly involved are the medial thalamus, mammillary bodies, periaqueductal gray matter, cerebellar vermis, and oculomotor, abducens, and vestibular nuclei.
Clinical Findings The classic syndrome comprises the triad of ophthalmoplegia, ataxia, and confusional state. The most common ocular abnormalities are nystagmus, abducens (VI) nerve palsy, and horizontal or combined horizontal-vertical gaze palsy. Ataxia affects gait primarily; ataxia of the arms is uncommon, as is dysarthria. The mental status examination reveals global confusion with a prominent disorder of immediate recall and recent memory. The confusional state progresses to coma in a small percentage of patients. Most patients have associated neuropathy with absent ankle jerks. Hypothermia and hypotension may occur due to hypothalamic involvement. Pupillary abnormalities, including mild anisocoria, or a sluggish reaction to light, are occasionally seen. The peripheral blood smear may show macrocytic anemia and MRI may show atrophy of the mammillary bodies.
Treatment Treatment requires prompt administration of thiamine. An initial dose of 100 mg is given intravenously, before or with dextrose, to avoid precipitating or exacerbating the disorder. Parenteral thiamine is continued for several days. The maintenance requirement for thiamine—about 1 mg/d—is usually available in the diet, although enteric absorption of thiamine is impaired in alcoholics.
Prognosis Following treatment, ocular abnormalities usually begin to improve within 1 day and ataxia and confusion within a week. Ophthalmoplegia, vertical nystagmus, and acute confusion are entirely reversible, usually
Vitamin B12 (cyanocobalamin) deficiency produces peripheral neuropathy, subacute combined degeneration of the spinal cord, nutritional amblyopia (visual loss), and cognitive dysfunction that ranges from a mild confusional state to dementia or psychosis (megaloblastic madness). Neurologic abnormalities may precede the development of macrocytic anemia. The most frequent cause of vitamin B12 deficiency is pernicious anemia, a defect in the production of intrinsic factor associated with gastric atrophy and achlorhydria, which is most common in those of northern European ancestry.
Clinical Findings The presenting symptoms are usually due to anemia or orthostatic lightheadedness, but may also be neurologic. Distal paresthesias, gait ataxia, a bandlike sensation of tightness around the trunk or limbs, and Lhermitte sign (an electric-shocklike sensation along the spine precipitated by neck flexion) may be present. Physical examination may show low-grade fever, glossitis, lemon-yellow discoloration of the skin, and cutaneous hyperpigmentation. Cerebral involvement produces confusion, depression, agitation, or psychosis with hallucinations. Spinal cord involvement is manifested by impaired vibratory and joint position sense, sensory gait ataxia and spastic paraparesis with extensor plantar responses. Associated peripheral nerve involvement may cause loss of tendon reflexes in the legs and urinary retention. Hematologic abnormalities include macrocytic anemia, leukopenia with hypersegmented neutrophils, and thrombocytopenia with giant platelets. Because folate deficiency can produce identical changes, the diagnosis must be confirmed by the serum vitamin B12 level. When this is low, Schilling test determines whether defective intestinal absorption of vitamin B12 (as in pernicious anemia) is the cause. In pernicious anemia, the urinary excretion of orally administered vitamin B12 is abnormally low, and this abnormality can be corrected by coadministration of intrinsic factor. Diagnosis may be difficult when cerebral symptoms occur without anemia or spinal cord disease, requiring that the serum vitamin B12 level be determined routinely in patients with cognitive disorders, myelopathy, or peripheral neuropathy, whether or not anemia is present.
Treatment Treatment of neurologic manifestations is by prompt intramuscular administration of cyanocobalamin, after
DISORDERS OF COGNITIVE FUNCTION / 19 blood is drawn to determine the serum vitamin B12 level. Daily injections are continued for 1 week, and Schilling test is performed to determine the cause of deficiency. If, as in pernicious anemia, deficiency is not correctable by dietary supplementation or treatment of intestinal malabsorption, intramuscular vitamin B12 (typically 100 µg) are given at weekly intervals for several months and monthly thereafter. The reversibility of neurologic complications depends upon their duration. Abnormalities present for more than 1 year are less likely to resolve with treatment. Encephalopathy may begin to clear within 24 hours after the first vitamin B12 dose, but full neurologic recovery, when it occurs, may take several months.
ORGAN SYSTEM FAILURE HEPATIC ENCEPHALOPATHY Hepatic encephalopathy occurs as a complication of cirrhosis, portosystemic shunting, chronic active hepatitis, or fulminant hepatic necrosis following viral hepatitis. Alcoholism is the most common underlying disorder. The syndrome may be chronic and progressive or acute in onset; in the latter case, gastrointestinal hemorrhage is a frequent precipitating cause. Liver disease produces cerebral symptoms by impairing hepatocellular detoxifying mechanisms or by the portosystemic shunting of venous blood. As a result, ammonia and other toxins accumulate in the blood and diffuse into the brain. Increased activity of γaminobutyric acid (GABA)-containing neuronal pathways in the brain and elevated levels of endogenous benzodiazepines may be involved in the pathogenesis of cerebral symptoms.
turing, and extensor plantar responses. Focal neurologic signs and focal or generalized seizures may occur. Laboratory studies may show elevated serum bilirubin, transaminases, ammonia, prothrombin time (PT) and partial thromboplastin time (PTT), and respiratory alkalosis. The most specific CSF abnormality is elevated glutamine (Figure 1–5). The EEG may be diffusely slow with triphasic waves.
Treatment Treatment includes restricting dietary protein, reversing electrolyte disturbances and hyperglycemia, discontinuing drugs that may have caused decompensation, providing antibiotics, and correcting coagulopathy with fresh-frozen plasma or vitamin K. Oral or rectal administration of lactulose, 20–30 g three or four times daily, decreases colonic pH and ammonia absorption. Neomycin, 1–3 g orally four times daily, may reduce ammonia-forming bacteria in the colon. Some success also has been reported with the benzodiazepine receptor antagonist flumazenil. Orthotopic liver transplantation is required in some cases. Prognosis in hepatic encephalopathy correlates best with the severity of hepatocellular rather than neurologic dysfunction.
REYE SYNDROME Reye syndrome is a rare disorder characterized by encephalopathy or coma with laboratory evidence of hepatic dysfunction. It usually occurs in children several days after a viral illness, especially varicella or influenza B. Administration of salicylates appears to be an additional risk factor. The incidence of Reye syndrome has declined dramatically in recent years, at least partly as a result of vaccination for varicella and the avoidance of aspirin in treating children with febrile illnesses.
Clinical Findings Hepatic encephalopathy
Other liver disease
Normal and other illnesses
100 Glutamine (mg/dL)
Symptoms of encephalopathy may precede systemic symptoms such as nausea, anorexia, and weight loss. Recent gastrointestinal bleeding, consumption of highprotein foods, use of sedatives or diuretics, or systemic infection may provide a clue to the cause of clinical decompensation. Physical examination may reveal systemic signs of liver disease. Cognitive disturbances include somnolence, agitation, and coma. Ocular reflexes are usually brisk. Nystagmus, tonic downward ocular deviation, and disconjugate eye movements may be seen. The most helpful neurologic sign of a metabolic disturbance, although not restricted to liver disease, is asterixis—a flapping tremor of the outstretched hands or feet that results from impaired postural control. Other motor abnormalities include tremor, myoclonus, paratonic rigidity, spasticity, decorticate or decerebrate pos-
80 60 40 20 0
Figure 1–5. Range of CSF glutamine concentrations in hepatic encephalopathy. (Reproduced, with permission, from Plum F: The CSF in hepatic encephalopathy. Exp Biol Med 1971;4:34–41.)
20 / CHAPTER 1
UREMIA Renal failure, particularly when acute in onset or rapidly progressive, may produce encephalopathy or coma with hyperventilation and prominent motor manifestations. These include tremor, asterixis, myoclonus, and tetany. Focal or generalized seizures and focal neurologic signs are common, and decorticate or decerebrate posturing may occur. Laboratory abnormalities include elevated serum urea nitrogen, creatinine and potassium, and metabolic acidosis, but their severity correlates poorly with symptoms. The EEG is diffusely slow and may show triphasic waves or paroxysmal spikes or sharp waves. Acute management includes hydration, protein and salt restriction, and treatment of complications such as seizures. Long-term management requires reversing the cause (eg, urinary tract obstruction), dialysis, or kidney transplantation. Although dialysis reverses the encephalopathy, clinical improvement often lags behind normalization of serum urea nitrogen and creatinine. Dialysis itself can produce an encephalopathy, termed dialysis disequilibrium syndrome, that is thought to result from hypoosmolality. This is most common with a patient’s first hemodialysis and can be prevented by correcting uremia more gradually or using briefer periods of dialysis at reduced rates of blood flow.
PULMONARY ENCEPHALOPATHY Patients with lung disease or brainstem or neurologic disorders that affect respiratory function may develop encephalopathy related to hypoventilation. Symptoms include headache, confusion, and somnolence. Examination shows papilledema, asterixis or myoclonus, and confusional state or coma. Tendon reflexes are often decreased, but pyramidal signs may be present, and seizures occur occasionally. Arterial blood gases show respiratory acidosis. Treatment involves ventilatory support to decrease hypercapnia and to maintain adequate oxygenation.
ORGAN TRANSPLANTATION Treatment of organ failure by transplantation can lead to acute confusional states as a consequence of surgical complications, immunosuppressive drug treatment, opportunistic infection, lymphoproliferative disorders, or transplant rejection. The problems encountered depend on the time in relation to transplantation and on the organ transplanted. Surgical complications that may produce encephalopathy include hypotension, hypoxia, thromboembolism, and air embolism, and are most common with heart and liver transplants. Immunosuppressive drugs used to prevent transplant rejection can cause acute confusional states by di-
rect effects on the nervous system or as a consequence of immunological impairment. Cyclosporine and tacrolimus (FK-506) produce encephalopathy that may be associated with seizures, tremor, visual disturbances, weakness, sensory symptoms, or ataxia. MRI shows abnormalities in the subcortical white matter. Symptoms are often associated with excessively high drug levels in the blood and may improve with reduction of drug dosage. Corticosteroids can produce psychosis, which may respond to substituting dexamethasone, and corticosteroid withdrawal is sometimes associated with lethargy, headache, myalgia, and arthralgia. OKT3 causes encephalopathy, aseptic meningitis, and seizures. Gabapentin is often used to treat seizures in transplant recipients because of its relative lack of pharmacokinetic interaction with other drugs typically given to these patients. Infections causing confusional states are most prominent following bone marrow transplantation, but are also common after transplantation of other organs. They are comparatively rare in the first month following transplantation and, when they occur, usually reflect preexisting infection in the recipient or in the donor organ, or a perioperative complication. Within this period, the most frequent organisms are gram-negative bacteria, herpes simplex virus, and fungi. Opportunistic infections are more common between 1 and 6 months posttransplant and include acute Listeria meningitis or encephalitis; chronic meningitis from Cryptococcus or Mycobacterium tuberculosis; and brain abscesses related to infection with Aspergillus, Nocardia, or Toxoplasma. Beyond 6 months, cytomegalovirus, Toxoplasma, Cryptococcus, Listeria, or Nocardia infection may be seen. Posttransplant lymphoproliferative disorder is related to immunosuppression and may be associated with primary central nervous system lymphoma. Transplant rejection may also produce encephalopathy, especially in recipients of kidney transplants.
MENINGITIS, ENCEPHALITIS, & SEPSIS BACTERIAL MENINGITIS Bacterial meningitis is a leading cause of acute confusional states and one in which early diagnosis greatly improves the outcome. Predisposing conditions include systemic (especially respiratory) or parameningeal infection, head trauma, anatomic meningeal defects, prior neurosurgery, cancer, alcoholism, and other immunodeficiency states. The etiologic organism varies with age and with the presence of predisposing conditions (Table 1–13).
DISORDERS OF COGNITIVE FUNCTION / 21 Table 1–13. Etiologic agents and empirical antibiotic treatment in bacterial meningitis, based on age and predisposing condition. Age or Condition
Etiologic Agents
Antibiotics of Choice
Less than 3 months
S agalactiae E coli L monocytogenes
Ampicillin, 100 mg/kg intravenously every 8 hours + cefotaxime, 50 mg/kg intravenously every 6 hours or ceftriaxone, 50–100 mg/kg intravenously every 12 hours
3 months to 8 years
N meningitidis S pneumoniae H influenzae
Cefotaxime, 50 mg/kg intravenously every 6 hours or ceftriaxone, 50–100 mg/kg intravenously every 12 hours + vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of 4 g/d
18 to 50 years
S pneumoniae N meningitidis
Cefotaxime, 2 g intravenously every 6 hours or ceftriaxone, 2 g intravenously every 12 hours + vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of 4 g/d
Older than 50 years
S pneumoniae L monocytogenes Gram-negative bacilli
Ampicillin, 2 g intravenously every 4 hours + cefotaxime, 2 g intravenously every 6 hours or ceftriaxone, 2 g intravenously every 12 hours
Impaired cellular immunity
L monocytogenes Gram-negative bacilli
Ampicillin, 100 mg/kg intravenously every 8 hours (neonate) or 2 g intravenously every 4 hours (adult) + ceftazidime, 50–100 mg/kg intravenously every 8 hours, to maximum of 2 g every 8 hours
Head trauma, neurosurgery, or CSF shunt
Staphylococci Gram-negative bacilli S pneumoniae
Vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of 4 g/d + ceftazidime, 50–100 mg/kg intravenously every 8 hours, to maximum of 2 g every 8 hours
Adapted from Quagliarello VJ, Scheld WM: Treatment of bacterial meningitis. N Engl J Med 1997;336:708–716.
Pathogenesis & Pathology Bacteria typically gain access to the central nervous system by colonizing the mucous membranes of the nasopharynx, leading to local tissue invasion, bacteremia, and hematogenous seeding of the subarachnoid space. Bacteria can also spread to the meninges directly, through anatomic defects in the skull or from parameningeal sites such as the paranasal sinuses or middle ear. Polysaccharide bacterial capsules, lipopolysaccharides, and outer membrane proteins may contribute to the bacterial invasion and virulence. The low levels of antibody and complement present in the subarachnoid space are inadequate to contain the infection. The resulting inflammatory response is associated with the re-
lease of inflammatory cytokines, including interleukins 1 and 6 and tumor necrosis factor α, that promote blood-brain barrier permeability, vasogenic cerebral edema, changes in cerebral blood flow, and perhaps direct neuronal toxicity. Pathologically, bacterial meningitis is characterized by leptomeningeal and perivascular infiltration with polymorphonuclear leukocytes and an inflammatory exudate. These changes tend to be most prominent over the cerebral convexities in Streptococcus pneumoniae and Haemophilus infection and over the base of the brain with Neisseria meningitidis. Brain edema, hydrocephalus, and cerebral infarction may occur, although actual bacterial invasion of the brain is rare.
22 / CHAPTER 1
Clinical Findings A. SYMPTOMS AND SIGNS At presentation, most patients have had symptoms of meningitis for 1 to 7 days. These include fever, confusion, vomiting, headache, and neck stiffness, but the full syndrome is often not present. Physical examination may show fever and signs of systemic or parameningeal infection, such as skin abscess or otitis. A petechial rash is seen in 50–60% of patients with N meningitidis meningitis. Signs of meningeal irritation are seen in about 80% of cases, but are often absent in the very young and very old, or with profoundly impaired consciousness. These signs include neck stiffness on passive flexion, thigh flexion upon flexion of the neck (Brudzinski sign), and resistance to passive extension of the knee with the hip flexed (Kernig sign). The level of consciousness, when altered, ranges from mild confusion to coma. Focal neurologic signs, seizures, and cranial nerve palsies may occur. B. LABORATORY FINDINGS Peripheral blood may reveal polymorphonuclear leukocytosis from systemic infection or leukopenia due to immunosuppression. The causative organism can be cultured from the blood in 40–90% of meningitis cases. X-rays of the chest, sinuses, or mastoid bones may indicate a primary site of infection. A brain CT or MRI scan may show contrast enhancement of the cerebral convexities, the base of the brain, or the ventricular ependyma. The EEG is usually diffusely slow, and focal abnormalities suggest the possibility of focal cerebritis, abscess formation, or scarring. Although these studies may be helpful, the essential test in all cases of suspected meningitis is prompt lumbar puncture and CSF examination. CSF pressure is elevated in about 90% of cases, and the appearance of the fluid ranges from slightly turbid to grossly purulent. CSF white cell counts of 1000–10,000/mL are usually seen, consisting chiefly of polymorphonuclear leukocytes, although mononuclear cells may predominate in Listeria monocytogenes meningitis. Protein concentrations of 100–500 mg/dL are most common. The CSF glucose level is lower than 40 mg/dL in about 80% of cases and may be too low to measure. Gram-stained smears of CSF identify the causative organism in 70–80% of cases. CSF culture, which is positive in about 80% of cases, provides a definitive diagnosis and allows determination of antibiotic sensitivity. The polymerase chain reaction has also been used with CSF specimens to diagnose bacterial meningitis, including H influenzae, N meningitidis, and L monocytogenes meningitis.
Differential Diagnosis Signs of meningeal irritation may also be seen with subarachnoid hemorrhage, but the distinction is easily
made because lumbar puncture yields bloody CSF in that condition. Early viral meningitis can produce polymorphonuclear pleocytosis and symptoms identical to those of bacterial meningitis, but a repeat lumbar puncture after 6–12 hours should demonstrate a shift to lymphocytic predominance in viral meningitis, and the CSF glucose level is normal.
Prevention Children should be routinely immunized against H influenzae by vaccination. A vaccine is also available for some strains of N meningitidis and is recommended for military recruits, college students, and travelers to areas of ongoing epidemics. The risk of contracting H influenzae or N meningitidis meningitis can be reduced in household and other close contacts of affected patients by the prophylactic administration of rifampin, 20 mg/kg/d orally, given as a single daily dose for 4 days (H influenzae) or as two divided doses for 2 days (N meningitidis).
Treatment Unless the physical examination shows focal neurologic abnormalities or papilledema, lumbar puncture should be performed immediately; if the CSF is not clear and colorless, antibiotic treatment (see below) is started without delay. When focal signs or papilledema are present, blood and urine should be taken for culture, antibiotics begun, and a brain CT scan obtained. If the scan shows no focal lesion that would contraindicate lumbar puncture, the puncture is then performed. The initial choice of antibiotics is empirical, based upon the patient’s age and predisposing factors (see Table 1–13). Therapy is adjusted as indicated when the Gram stain or culture and sensitivity results become available (Table 1–14). Lumbar puncture can be repeated to assess the response to therapy. CSF should be sterile after 24 hours, and a decrease in pleocytosis and in the proportion of polymorphonuclear leukocytes should occur within 3 days. Dexamethasone, given immediately before the onset of antibiotic treatment and continued every 6 hours for 4 days, can improve outcome and decrease mortality in bacterial meningitis.
Prognosis Complications of bacterial meningitis include headache, seizures, hydrocephalus, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), residual neurologic deficits (including cognitive disturbances and cranial—especially VIII—nerve abnormalities), and death. A CT scan will confirm suspected hydrocephalus and fluid and electrolyte status should be carefully monitored to detect SIADH. N meningitidis
DISORDERS OF COGNITIVE FUNCTION / 23 Table 1–14. Treatment of bacterial meningitis of known cause.
Etiologic Agents Gram’s stain Cocci Gram-positive
Gram-negative
Bacilli Gram-positive
Gram-negative
CSF culture S pneumoniae
Antibiotics of Choice
Duration of Tretament (days)
Vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of 4 g/d; substitute rifampin (600 mg/d) for vancomycin in adults receiving dexamethasone + cefotaxime, 50 mg/kg intravenously every 6 hours (neonates) or ceftriaxone, 50–100 mg/kg intravenously every 12 hours (children); 2 g intravenously every 12 hours (adults)
—
Penicillin G, 300,000 units/kg/d intravenously, to maximum of 24 million units/d
—
Ampicillin, 100 mg/kg intravenously every 8 hours (children); 2 g intravenously every 4 hours (adults) or penicillin G, 300,000 units/kg/d intravenously, to maximum of 24 million units/d + gentamicin, 1.5 mg/kg intravenous loading dose followed by 1–2 mg/kg intravenously every 8 hours
—
Cefotaxime, 50 mg/kg intravenously every 6 hours (neonates) or ceftriaxone, 50–100 mg/kg intravenously every 12 hours (children); 2 g intravenously every 12 hours (adults) or ceftazidime, 50–100 mg/kg intravenously every 8 hours, to maximum of 2 g every 8 hours + gentamicin, 1.5 mg/kg intravenous loading dose followed by 1–2 mg/kg intravenously every 8 hours
—
Vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of 4 g/d; substitute rifampin (600 mg/d) for vancomycin in adults receiving dexamethasone + cefotaxime, 50 mg/kg intravenously every 6 hours (neonates) or ceftriaxone, 50–100 mg/kg intravenously every 12 hours (children); 2 g intravenously every 12 hours (adults)
10–14
H influenzae
Ceftriaxone, 50–100 mg/kg intravenously every 12 hours (children); 2 g intravenously every 12 hours (adults)
7
N meningitidis
Penicillin G, 300,000 units/kg/d intravenously, to maximum of 24 million units/d
7
L monocytogenes
Ampicillin, 100 mg/kg intravenously every 8 hours (children); 2 g intravenously every 4 hours (adults) + gentamicin, 1.5 mg/kg intravenous loading dose followed by 1–2 mg/kg intravenously every 8 hours
14–21
S. agalactiae
Penicillin G, 300,000 units/kg/d intravenously, to maximum of 24 million units/d
14–21
(continued)
24 / CHAPTER 1 Table 1–14. Treatment of bacterial meningitis of known cause. (continued)
Etiologic Agents
Antibiotics of Choice
Duration of Tretament (days)
Enterobacteriaceae
Cefotaxime, 50 mg/kg intravenously every 6 hours (neonates) or ceftriaxone, 50–100 mg/kg intravenously every 12 hours (children); 2 g intravenously every 12 hours (adults) + gentamicin, 1.5 mg/kg intravenous loading dose followed by 1–2 mg/kg intravenously every 8 hours
21
Pseudomonas aeruginosa, acinetobacter
Ceftazidime, 50–100 mg/kg intravenously every 8 hours, to maximum of 2 g every 8 hours + gentamicin, 1.5 mg/kg intravenous loading dose followed by 1–2 mg/kg intravenously every 8 hours
21
Adapted from Quagliarello VJ, Scheld WM: Treatment of bacterial meningitis. N Engl J Med 1997;336:708–716.
infections may be complicated by adrenal hemorrhage related to meningococcemia, resulting in hypotension and often death (Waterhouse-Friderichsen syndrome). Morbidity and mortality from bacterial meningitis are high. Fatalities occur in about 20% of affected adults, and more often with some pathogens (eg, S pneumoniae, gram-negative bacilli) than others (eg, H influenzae, N meningitidis). Factors that worsen prognosis include extremes of age, delay in diagnosis and treatment, complicating illness, stupor or coma, seizures, and focal neurologic signs.
TUBERCULOUS MENINGITIS Tuberculous meningitis must be considered in patients who present with a confusional state, especially if there is a history of pulmonary tuberculosis, alcoholism, corticosteroid treatment, HIV infection, or other conditions associated with impaired immune responses. It should also be considered in patients from areas (eg, Asia, Africa) or groups (eg, the homeless and inner-city drug users) with a high incidence of tuberculosis.
Pathogenesis & Pathology Tuberculous meningitis usually results from reactivation of latent infection with Mycobacterium tuberculosis. Primary infection, typically acquired by inhaling bacillus-containing droplets, may be associated with metastatic dissemination of blood-borne bacilli from the lungs to the meninges and the surface of the brain. Here the organisms remain in a dormant state in tubercles that can rupture into the subarachnoid space at a later time, resulting in tuberculous meningitis.
The main finding is a basal meningeal exudate containing primarily mononuclear cells. Tubercles may be seen on the meninges and surface of the brain. The ventricles may be enlarged as a result of hydrocephalus, and their surfaces may show ependymal exudate or granular ependymitis. Arteritis can result in cerebral infarction, and basal inflammation and fibrosis can compress cranial nerves.
Clinical Findings A. SYMPTOMS AND SIGNS Symptoms usually have been present for less than 4 weeks at the time of presentation and include fever, lethargy or confusion, and headache. Weight loss, vomiting, neck stiffness, visual impairment, diplopia, focal weakness, and seizures may also occur. A history of contact with known cases of tuberculosis is usually absent. Fever, signs of meningeal irritation, and a confusional state are the most common findings on physical examination, but all may be absent. Papilledema, ocular palsies, and hemiparesis are sometimes seen. Complications include spinal subarachnoid block, hydrocephalus, brain edema, cranial nerve palsies, and stroke caused by vasculitis or compression of blood vessels at the base of the brain. B. LABORATORY FINDINGS Only one-half to two-thirds of patients show a positive skin test for tuberculosis or evidence of active or healed tubercular infection on chest x-ray. The diagnosis is established by CSF analysis. CSF pressure is usually in-
DISORDERS OF COGNITIVE FUNCTION / 25 creased, and the fluid is typically clear and colorless but may form a clot upon standing. Lymphocytic and mononuclear cell pleocytosis of 50–500 cells/mL is most often seen, but polymorphonuclear pleocytosis can occur early and may give an erroneous impression of bacterial meningitis. CSF protein is usually more than 100 mg/dL and may exceed 500 mg/dL, particularly in patients with spinal subarachnoid block. The glucose level is usually decreased and may be less than 20 mg/dL. Acid-fast smears of CSF should be performed in all cases of suspected tuberculous meningitis, but they are positive in only a minority of cases. Definitive diagnosis is most often made by culturing M tuberculosis from the CSF, a process that usually takes several weeks and requires large quantities of spinal fluid for maximum yield. However, the polymerase chain reaction has also been used for diagnosis. Finally, the CT scan may show contrast enhancement of the basal cisterns and cortical meninges, or hydrocephalus.
Differential Diagnosis Many other conditions can cause a subacute confusional state with mononuclear cell pleocytosis, including syphilitic, fungal, neoplastic, and partially treated bacterial meningitis. These can be diagnosed by appropriate smears, cultures, and serologic and cytologic examinations.
Treatment Treatment should be started as early as possible; it should not be withheld while awaiting culture results. The decision to treat is based on the CSF findings described above; lymphocytic pleocytosis and decreased glucose are particularly suggestive, even if acid-fast smears are negative. Four drugs are used for initial therapy, until culture and susceptibility test results are known. These are isoniazid, 300 mg; rifampin, 600 mg; pyrazinamide, 25 mg/kg; and ethambutol, 15 mg/kg, each given orally once daily. For susceptible strains, ethambutol can be discontinued, and triple therapy continued for 2 months, followed by 4–10 months of treatment with isoniazid and rifampin alone. Pyridoxine, 50 mg/d, can be used to decrease the likelihood of isoniazid-induced polyneuropathy. Complications of therapy include hepatic dysfunction (isoniazid, rifampin, and pyrazinamide), polyneuropathy (isoniazid), optic neuritis (ethambutol), seizures (isoniazid), and ototoxicity (streptomycin). Corticosteroids (eg, prednisone, 60 mg/d orally in adults or 1–3 mg/kg/d orally in children, tapered gradually over 3–4 weeks) are indicated as adjunctive therapy in patients with spinal subarachnoid block. They also may be indicated in seriously ill patients with focal
neurologic signs or with increased intracranial pressure from cerebral edema. The risk of using corticosteroids may be high, however, especially if tuberculous meningitis has been mistakenly diagnosed in a patient with fungal meningitis. Therefore, if fungal meningitis has not been excluded, antifungal therapy (see below) should be added along with corticosteroids.
Prognosis Even with appropriate treatment, about one-third of patients with tuberculous meningitis succumb. Coma at the time of presentation is the most significant predictor of a poor prognosis.
SYPHILITIC MENINGITIS Acute or subacute syphilitic meningitis usually occurs within 2 years after primary syphilitic infection. It is most common in young adults, affects men more often than women, and requires prompt treatment to prevent the irreversible manifestations of tertiary neurosyphilis. In about one-fourth of patients with Treponema pallidum infection, treponemes gain access to the central nervous system, where they produce a meningitis that is usually asymptomatic (asymptomatic neurosyphilis). Asymptomatic invasion of the central nervous system is associated with CSF pleocytosis, elevated protein, and positive serologic tests for syphilis.
Clinical Findings A. SYMPTOMS AND SIGNS In a few patients, syphilitic meningitis is a clinically apparent acute or subacute disorder. At the time of presentation, symptoms such as headache, nausea, vomiting, stiff neck, mental disturbances, focal weakness, seizures, deafness, and visual impairment usually have been present for up to 2 months. Physical examination may show signs of meningeal irritation, confusion or delirium, papilledema, hemiparesis, and aphasia. The cranial nerves most frequently affected are (in order) the facial (VII), acoustic (VIII), oculomotor (III), trigeminal (V), abducens (VI), and optic (II) nerves, but other nerves may be involved as well. Fever is typically absent. B. LABORATORY FINDINGS The diagnosis is established by CSF findings. Opening pressure is normal or slightly elevated. Pleocytosis is lymphocytic or mononuclear in character, with white cell counts usually in the range of 100–1000/mL. Protein may be mildly or moderately elevated (<200 mg/dL) and glucose mildly decreased. CSF VDRL and serum FTA or MHA-TP tests are usually positive. Protein electrophoretograms of CSF may show discrete γ-
26 / CHAPTER 1 globulin bands (oligoclonal bands) not visible in normal CSF.
Treatment Acute syphilitic meningitis is usually a self-limited disorder with no or minimal sequelae. More advanced manifestations of neurosyphilis, including vascular and parenchymatous disease (eg, tabes dorsalis, general paresis, optic neuritis, myelitis), can be prevented by adequate treatment of the early syphilitic infection. Syphilitic meningitis is treated with aqueous penicillin G, 2–4 × 106 units intravenously every 4 hours for 10 days. For penicillin-allergic patients, tetracycline or erythromycin, 500 mg orally every 6 hours for 20 days, can be substituted. The CSF should be examined every 6 months until all findings are normal. Another course of therapy must be given if the CSF cell count or protein remains elevated.
LYME DISEASE Clinical Findings Lyme disease is a tick-borne disorder that results from systemic infection with the spirochete Borrelia burgdorferi. Most cases occur during the summer months. Primary infection may be manifested by an expanding erythematous annular skin lesion (erythema migrans) that usually appears over the thigh, groin, or axilla. Less distinctive symptoms include fatigue, headache, fever, neck stiffness, joint or muscle pain, anorexia, sore throat, and nausea. Neurologic involvement may be delayed for up to 10 weeks and is characterized by meningitis or meningoencephalitis and disorders of the cranial or peripheral nerves or nerve roots. Cardiac abnormalities (conduction defects, myocarditis, pericarditis, cardiomegaly, or heart failure) can also occur at this stage. Lyme meningitis usually produces prominent headache that may be accompanied by signs of meningeal irritation, photophobia, pain when moving the eyes, nausea, and vomiting. When encephalitis is present, it is usually mild and characterized by insomnia, emotional lability, or impaired concentration and memory. The CSF usually shows a lymphocytic pleocytosis with 100–200 cells/mL, slightly elevated protein, and normal glucose. Oligoclonal immunoglobulin G (IgG) bands may be detected. Definitive diagnosis is usually made by serologic testing for B burgdorferi, preferably by enzyme-linked immunosorbent assay (ELISA) followed by Western blot, but the polymerase chain reaction, which can amplify spirochetal DNA in synovial fluid, blood, or CSF, has also been used.
Treatment Preventive measures include avoiding tick-infested areas and using insect repellents and protective clothing
when avoidance is impossible. A Lyme disease vaccine is also available, but its use is controversial. For patients with Lyme disease and Bell palsy, treatment is with doxycycline (100 mg twice daily) or amoxicillin (500 mg three times daily), each given orally for 3–4 weeks. With meningitis or other central nervous system (CNS) involvement, intravenous treatment is indicated with ceftriaxone (2 g intravenously daily), penicillin G (20–24 million units intravenously daily in six divided doses), or cefotaxime (2 g intravenously every 8 hours), continued for 2–4 weeks. Symptoms typically resolve within 10 days in treated cases. Untreated or inadequately treated infections may lead to recurrent oligoarthritis, and chronic neurologic disorders including memory, language, and other cognitive disturbances; focal weakness; and ataxia. In such cases, a CT scan or MRI may show hydrocephalus, lesions in white matter resembling those seen in multiple sclerosis, or abnormalities suggestive of cerebral infarction. Subtle chronic cognitive or behavioral symptoms should not be attributed to Lyme encephalitis in the absence of serologic evidence of B burgdorferi exposure, CSF abnormalities, or focal neurologic signs. The peripheral neurologic manifestations of Lyme disease are discussed in Chapter 6.
VIRAL MENINGITIS & ENCEPHALITIS Viral infections of the meninges (meningitis) or brain parenchyma (encephalitis) often present as acute confusional states. Children and young adults are frequently affected. Viral meningitis is most often caused by enteric viruses (Table 1–15) and viral encephalitis by childhood exanthems, arthropod-borne agents, and herpes simplex type 1 (Table 1–16). Some forms of viral encephalitis tend to show a restricted geographic distribution. However, the speed and volume of international travel can permit these disorders to spread, as was observed recently for West Nile virus in the northeastern United States.
Pathology Viral infections can affect the central nervous system in three ways—hematogenous dissemination of a systemic viral infection (eg, arthropod-borne viruses); neuronal spread of the virus by axonal transport (eg, herpes simplex, rabies); and autoimmune postinfectious demyelination (eg, varicella, influenza). Pathologic changes in viral meningitis consist of an inflammatory meningeal reaction mediated by lymphocytes. Encephalitis is characterized by perivascular cuffing, lymphocytic infiltration, and microglial proliferation mainly involving subcortical gray matter regions. Intranuclear or intracytoplasmic inclusions are often seen.
DISORDERS OF COGNITIVE FUNCTION / 27 Table 1–15. Etiologic agents in viral meningitis. Virus
Seasonal Variation
Incidence
Source
Susceptible Population
Systemic Involvement
Laboratory Findings −
Echoviruses
30%
Summer, fall
Fecal-oral
Children, Maculopapular, members of vesicular, or affected families petechial skin rash; gastroenteritis
Coxsackievirus A
10%
Summer, fall
Fecal-oral
Children, Maculopapular, − members of vesicular, or affected families petechial skin rash; herpangina; gastroenteritis
Coxsackievirus B
40%
Summer, fall
Fecal-oral
Children, Maculopapular, members of vesicular, or affected families petechial skin rash; pleuritis, pericarditis, myocarditis, orchitis; gastroenteritis
Mumps virus
15%
Late winter, spring
Inhalation
Children, male more than female
Parotitis, orchitis, Amylase ↑; CSF oophoritis, glucose may pancreatitis be ↑ or ↓
Herpes simplex virus (type 2)
Uncommon
—
Genital infection
Neonates with affected mothers
Vesicular genital lesions
Adenovirus
Uncommon
—
Inhalation
Infants, children Pharyngitis, pneumonitis
−
Lymphocytic Uncommon choriomeningitis virus
Late fall, winter
Mouse
Laboratory workers
Pharyngitis, pneumonitis
Marked CSF pleocytosis (1000–10,000 WBC/µL)
Hepatitis viruses
Uncommon
—
Fecal-oral, venereal, transfusion
Intravenous drug users, male homosexuals, blood recipients
Jaundice, arthritis
Liver function abnormalities
Epstein-Barr virus Uncommon (infectious mononucleosis)
—
Oral contact
Teenagers, young adults
Lymphadenopathy, pharyngitis, maculopapular skin rash, palatal petechiae, splenomegaly
Atypical lymphocytes, positive heterophil, liver function abnormalities
−
−
Table 1–16. Etiologic agents in viral encephalitis. Type of Encephalitis
Vector
Geographic Distribution
Comments
Childhood exanthems Measles, varicella, mumps, rubella
Human
Arthropod-borne (Arbo) viruses Alphaviruses Eastern equine Mosquito
Worldwide
Uncommon in USA because of vaccination
USA (Atlantic and Gulf coasts), Caribbean, South America
Children usually affected; mortality 50–75%; neurologic sequelae common
Western equine
Mosquito
Western and central USA, South America
Infants and adults >50 years usually affected; mortality 5–15%; neurologic sequelae uncommon except in infants
Venezuelan equine
Mosquito
Florida, southwestern USA, Central and South America
Adults usually affected; mortality 1%; neurologic sequelae rare
Flaviviruses Japanese B
Mosquito
China, Southeast Asia, India, Japan
Vaccine available
St. Louis
Mosquito
USA (rural west and midwest, New Jersey, Florida,Texas), Caribbean, Central and South America
Adults >50 years most often affected; mortality 2–20%; neurologic sequelae in about 20%
Murray Valley
Mosquito
Australia, New Guinea
West Nile
Mosquito
Middle East, Africa, Europe, Central Asia, northeastern USA
Rocio
Mosquito
Brazil
Kyasanur Forest
Tick
India
Powassan
Tick
New York, Ontario
Russian spring-summer
Tick
Northern Europe, Siberia
Louping-ill
Tick
United Kingdom
Mosquito
North America
Mosquito
Africa
Tick
Western and Rocky Mountain states of USA
Other Herpes simplex (type 1)
Human
Worldwide
Focal neurologic signs common; responds to treatment with acyclovir
Herpes simplex (type 2)
Human
Worldwide
Encephalitis usually affects neonates; causes meningitis in older children and adults
Wild and domestic mammals
Worldwide
Invariably fatal unless vaccine and antiserum administered before symptoms occur following bite by affected animal
Bunyaviruses California (including LaCrosse) Rift Valley
Orbiviruses Colorado tick fever
Rabies
Children usually affected; mortality < 1%; neurologic sequelae uncommon
DISORDERS OF COGNITIVE FUNCTION / 29
Clinical Findings A. SYMPTOMS AND SIGNS Clinical manifestations include fever, headache, neck stiffness, photophobia, pain with eye movement, and mild impairment of consciousness. Patients usually do not appear as ill as those with bacterial meningitis. Systemic viral infection may cause skin rash, pharyngitis, lymphadenopathy, pleuritis, carditis, jaundice, organomegaly, diarrhea, or orchitis, and these findings may suggest a particular etiologic agent. Because viral encephalitis involves the brain directly, marked alterations of consciousness, seizures, and focal neurologic signs can occur. When signs of meningeal irritation and brain dysfunction coexist, the condition is termed meningoencephalitis. B. LABORATORY FINDINGS CSF analysis is the most important laboratory test. CSF pressure is normal or increased, and a lymphocytic or monocytic pleocytosis is present, with cell counts usually less than 1000/mL. (Higher counts can be seen in lymphocytic choriomeningitis or herpes simplex encephalitis.) A polymorphonuclear pleocytosis can occur early in viral meningitis, while red blood cells may be seen with herpes simplex encephalitis. Protein is normal or slightly increased (usually 80–200 mg/dL). Glucose is usually normal, but may be decreased in mumps, herpes zoster, or herpes simplex encephalitis. Gram stains and bacterial, fungal, and acid-fast bacillus (AFB) cultures are negative. Oligoclonal bands and CSF protein electrophoresis abnormalities may be present. An etiologic diagnosis often can be made by virus isolation, polymerase chain reaction, or acute- and convalescent-phase CSF antibody titers. Blood counts may show a normal white cell count, leukopenia, or mild leukocytosis. Atypical lymphocytes in blood smears and a positive heterophil (Monospot) test suggest infectious mononucleosis. Serum amylase is frequently elevated in mumps; abnormal liver function tests are associated with both hepatitis viruses and infectious mononucleosis. The EEG is diffusely slow, especially if there is direct cerebral involvement.
Differential Diagnosis The differential diagnosis of meningitis with mononuclear cell pleocytosis includes partially treated bacterial meningitis as well as syphilitic, tuberculous, fungal, parasitic, neoplastic, and other meningitides. Evidence of systemic viral infection and CSF wet mounts, stained smears, cultures, and cytologic examination can distinguish among these possibilities. When presumed early viral meningitis is associated with a polymorphonuclear pleocytosis of less than 1000 white blood cells/mL and normal CSF glucose, one of two strategies
can be used. The patient can be treated for bacterial meningitis until the results of CSF cultures are known, or treatment can be withheld and lumbar puncture repeated in 6–12 hours. If the meningitis is viral in origin, the second sample should show a mononuclear cell pleocytosis. A disorder that may be clinically indistinguishable from viral encephalitis is the immune-mediated encephalomyelitis that may follow viral infections such as influenza, measles, or chickenpox. Progressive neurologic dysfunction typically begins a few days after the viral illness but can also occur either simultaneously or up to several weeks later. Neurologic abnormalities result from perivenous demyelination, which often severely affects the brainstem. The CSF shows a lymphocytic pleocytosis, usually with cell counts of 50–150/mL, and mild protein elevation.
Treatment Except for herpes simplex encephalitis, which is discussed separately (see below), no specific therapy for viral meningitis and encephalitis is available. Corticosteroids are of no proven benefit except in immunemediated postinfectious syndromes. Headache and fever can be treated with acetaminophen, but aspirin should be avoided, especially in children and young adults, because of its association with Reye syndrome (see p. 19). Seizures usually respond to phenytoin or phenobarbital. Supportive measures in comatose patients include mechanical ventilation and intravenous or nasogastric feeding.
Prognosis Symptoms of viral meningitis usually resolve spontaneously within 2 weeks regardless of the causative agent, although residual deficits may be seen. The outcome of viral encephalitis varies with the specific virus—for example, eastern equine and herpes simplex virus infections are associated with severe morbidity and high mortality rates. Mortality rates as high as 20% have also been reported in immune-mediated encephalomyelitis following measles infections.
HERPES SIMPLEX VIRUS (HSV) ENCEPHALITIS HSV is the most common cause of sporadic fatal encephalitis in the United States. About two-thirds of cases involve patients over 40 years of age. Primary herpes infections most often present as stomatitis (HSV type 1) or a venereally transmitted genital eruption (HSV type 2). The virus migrates along nerve axons to sensory ganglia, where it persists in a latent form and may be subsequently reactivated. It is not clear whether
30 / CHAPTER 1 HSV type 1 encephalitis, the most common type in adults, represents a primary infection or a reactivation of latent infection. Neonatal HSV encephalitis usually results from acquisition of type 2 virus during passage through the birth canal of a mother with active genital lesions. Central nervous system involvement by HSV type 2 in adults usually causes meningitis, rather than encephalitis.
Pathology HSV type 1 encephalitis is an acute, necrotizing, asymmetric hemorrhagic process with lymphocytic and plasma cell reaction, and usually involves the medial temporal and inferior frontal lobes. Intranuclear inclusions may be seen in neurons and glia. Patients who recover may show cystic necrosis of the involved regions.
Clinical Findings A. SYMPTOMS AND SIGNS The clinical syndrome may include headache, stiff neck, vomiting, behavioral disorders, memory loss, anosmia, aphasia, hemiparesis, and focal or generalized seizures. Active herpes labialis is seen occasionally, but does not reliably implicate HSV as the cause of encephalitis. HSV encephalitis is usually rapidly progressive over several days and may result in coma or death. The most common sequelae in patients who survive are memory and behavior disturbances, reflecting the predilection of HSV for limbic structures. B. LABORATORY FINDINGS The CSF in HSV type 1 encephalitis most often shows increased pressure, lymphocytic or mixed lymphocytic and polymorphonuclear pleocytosis (50–100 white blood cells/mL), mild protein elevation, and normal glucose. Red blood cells, xanthochromia, and decreased glucose are seen in some cases. The virus generally cannot be isolated from the CSF, but viral DNA has been detected by the polymerase chain reaction in some cases. The EEG may show periodic slow-wave complexes arising from one or both temporal lobes, and CT scans and MRI may show abnormalities in one or both temporal lobes. These can extend to frontal or parietal regions and are sometimes enhanced with the infusion of contrast material (Figure 1–6). However, imaging studies may also be normal.
Figure 1–6. T2-weighted MRI in herpes simplex encephalitis. Note the lack of differentiation between gray and white matter, because of edema, in the left anterior temporal lobe (arrows) compared with the right. (Courtesy of A Gean.)
tive diagnosis can be made by biopsy of affected brain areas, with the choice of biopsy site guided by the EEG, CT, or MRI findings. However, because treatment is most effective when begun early and is comparatively safe, the most common approach is to treat patients with possible HSV encephalitis as described below and to reserve biopsy for those who fail to improve.
Treatment The most effective drug is acyclovir, given intravenously at a dosage of 10–15 mg/kg every 8 hours, with each dose given over 1 hour. Treatment is continued for 14–21 days. Complications include erythema at the infusion site, gastrointestinal disturbances, headache, skin rash, tremor, seizures, and encephalopathy or coma. Treatment is started as early as possible, since outcome is greatly influenced by the severity of dysfunction at the time treatment is initiated.
Differential Diagnosis The symptoms and signs are not specific for herpes virus infection. The greatest diagnostic difficulty is distinguishing between HSV encephalitis and brain abscess, and the two disorders often cannot be differentiated on clinical grounds alone. Other CNS infections and vasculitis can also mimic HSV encephalitis. Defini-
Prognosis Patients under the age of 30 years and those who are only lethargic at the onset of treatment are more likely to survive than are older or comatose patients. The mortality rate is about 25% at 18 months in patients given acyclovir.
DISORDERS OF COGNITIVE FUNCTION / 31
ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) AIDS is caused by infection with human immunodeficiency virus type 1 (HIV-1) and is characterized by opportunistic infections, malignant neoplasms (typically non-Hodgkin lymphoma or Kaposi sarcoma), and a variety of neurologic disturbances. Transmission occurs through sexual activity or by transfer of virus-contaminated blood or blood products. Individuals at particular risk of infection include those who engage in unprotected sexual intercourse, intravenous drug users who share needles, hemophiliacs who have received factor VIII transfusions, and their sexual partners. Neurologic complications of AIDS include dementia (see below), myelopathy (see Chapter 5), neuropathy (see Chapter 6), myopathy (see Chapter 5), and stroke (see Chapter 9). In addition to the disorders that produce acute confusional states in persons without AIDS, patients with AIDS are at increased risk for direct HIV infection of the nervous system, other opportunistic infections, and certain tumors (Table 1–17). Treatment of AIDS is discussed in the section on AIDS dementia complex later in this chapter. 1. HIV-1 MENINGITIS Patients infected with HIV-1 can develop a syndrome characterized by headache, fever, signs of meningeal irritation, cranial nerve (especially VII) palsies, other focal neurologic abnormalities, or seizures. This usually occurs at about the time of HIV-1 seroconversion. An acute confusional state is occasionally present. HIV-1 meningitis is associated with mononuclear pleocytosis of up to about 200 cells/mL. Symptoms usually resolve spontaneously within about 1 month. Other causes of Table 1–17. Causes of acute confusional states in patients with AIDS. Meningitis HIV-1 meningitis Cryptococcal meningitis Encephalitis Herpes simplex encephalitis Varicella-zoster encephalitis Cytomegalovirus encephalitis Intracerebral mass lesions Cerebral toxoplasmosis Primary central nervous system lymphoma Metabolic encephalopathies Pulmonary encephalopathy (related to Pneumocystis carinii-pneumonia) Drug toxicity Stroke Seizures
pleocytosis associated with AIDS, including cryptococcal meningitis, herpes simplex encephalitis, and cerebral toxoplasmosis, must be excluded. 2. CRYPTOCOCCAL MENINGITIS Cryptococcal meningitis occurs in 5–10% of patients with AIDS. Clinical features include headache, confusion, stiff neck, fever, nausea and vomiting, seizures, and cranial nerve palsies. Because the CSF is otherwise normal in about 20% of patients with AIDS and cryptococcal meningitis, CSF cryptococcal antigen titers should always be obtained. Laboratory abnormalities and recommended treatment are discussed in the section on fungal meningitis below. 3. HERPES SIMPLEX & VARICELLA-ZOSTER ENCEPHALITIS Whereas HSV encephalitis in immunocompetent adults is almost always due to type 1 virus, either type 1 or type 2 HSV can produce the disorder in patients with AIDS. The focal neurologic signs and CSF abnormalities usually associated with HSV encephalitis may be absent in AIDS, and the disorder may follow a more indolent course. Varicella-zoster virus, a herpesvirus that rarely causes encephalitis in immunocompetent individuals, may do so in patients with AIDS. Treatment is as described above for HSV encephalitis. 4. CYTOMEGALOVIRUS ENCEPHALITIS Cytomegalovirus, another herpesvirus, has been implicated as a cause of retinitis and polyradiculomyelitis (see Chapter 5) in patients with AIDS. Cytomegalovirus can also be identified in CSF and biopsy specimens from patients with AIDS who are neurologically asymptomatic, acutely confused, or demented. Death usually occurs within a few weeks, although therapeutic responses to antiviral treatment with ganciclovir and foscarnet have been reported. 5. CEREBRAL TOXOPLASMOSIS Cerebral toxoplasmosis produces intracerebral mass lesions in patients with AIDS, although its frequency appears to be declining as antitoxoplasma drugs such as trimethoprim-sulfamethoxazole are widely used for prophylaxis against Pneumocystis carinii pneumonia in patients with AIDS. A confusional state lasting days to weeks exists at the time of presentation in about 30% of patients. Other clinical features include fever, focal neurologic abnormalities such as cranial nerve palsies or hemiparesis, seizures, headache, and signs of meningeal irritation. Serologic tests for toxoplasmosis are unreliable in patients with AIDS. MRI is more sensitive than CT scanning and typically reveals one or more lesions, which often show a contrast enhancement of the rim and are commonly located in the basal ganglia. Because toxoplasmosis is readily treatable, patients with AIDS and intracerebral mass lesions that are not
32 / CHAPTER 1 obviously due to stroke should be treated for presumed toxoplasmosis, as described in the section on parasitic infections below. Up to 90% of patients respond favorably to therapy within the first few weeks and the majority survive longer than 6 months. 6. PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA Primary central nervous system lymphoma is the most common brain tumor associated with AIDS. Systemic non-Hodgkin lymphoma also occurs with increased frequency, but usually produces lymphomatous meningitis (see below) rather than intracerebral masses. Clinical features of primary central nervous system lymphoma include confusional state, hemiparesis, aphasia, seizures, cranial nerve palsies, and headache; signs of meningeal irritation are uncommon. CSF commonly shows elevated protein and mild mononuclear pleocytosis, and glucose may be low; cytology is rarely positive. MRI is more sensitive than CT scanning and shows single or multiple contrast-enhanced lesions, which may not be distinguishable from those seen with toxoplasmosis. Patients with AIDS and one or more intracerebral mass lesions that fail to respond to treatment for toxoplasmosis within 3 weeks should undergo brain biopsy for diagnosis of lymphoma. Although corticosteroids and radiation therapy may prolong survival, most patients die within a few months. 7. OTHER DISORDERS Pneumocystis carinii pneumonia in patients with AIDS may lead to hypoxia and a resulting confusional state. Patients with AIDS, especially those with central nervous system involvement, may be especially sensitive to drugs (eg, antidepressants) and metabolic disorders, and the antiretroviral drug zidovudine can produce a confusional state. Stroke can occur in patients with AIDS, especially when it is complicated by cryptococcal meningitis, and may produce an acute confusional state. Seizures are common in patients with AIDS, especially those with AIDS dementia complex, cerebral toxoplasmosis, or cryptococcal meningitis, and both complex partial seizures and the postictal state that follows generalized tonic-clonic seizures are associated with confusional states.
FUNGAL MENINGITIS In a small fraction of patients with systemic fungal infections (mycoses), fungi invade the central nervous system to produce meningitis or focal intraparenchymal lesions (Table 1–18). Several fungi are opportunistic organisms that cause infection in patients with cancer, those receiving corticosteroids or other immunosuppressive drugs, and other debilitated hosts. Intravenous drug abuse is a potential route for infection with Candida and Aspergillus. Diabetic acidosis is strongly corre-
lated with rhinocerebral mucormycosis. In contrast, meningeal infections with Coccidioides, Blastomyces, and Actinomyces usually occur in previously healthy individuals. Cryptococcus (the most common cause of fungal meningitis in the United States) and Histoplasma infection can occur in either healthy or immunosuppressed patients. Cryptococcal meningitis is the most common fungal infection of the nervous system in AIDS, but Coccidioides and Histoplasma infections can also occur in this setting. Geographic factors are also important in the epidemiology of certain mycoses (see Table 1–18).
Pathogenesis & Pathology Fungi reach the central nervous system by hematogenous spread from the lungs, heart, gastrointestinal or genitourinary tract, or skin, or by direct extension from parameningeal sites such as the orbits or paranasal sinuses. Invasion of the meninges from a contiguous focus of infection is particularly common in mucormycosis but may also occur in aspergillosis and actinomycosis. Pathologic findings in fungal infections of the nervous system include a primarily mononuclear meningeal exudative reaction, focal abscesses or granulomas in the brain or spinal epidural space, cerebral infarction related to vasculitis, and ventricular enlargement caused by communicating hydrocephalus.
Clinical Findings Fungal meningitis is usually a subacute illness that clinically resembles tuberculous meningitis. A history of a predisposing condition such as carcinoma, hematologic malignancy, AIDS, diabetes, organ transplantation, treatment with corticosteroids or cytotoxic agents, prolonged antibiotic therapy, or intravenous drug use increases the suspicion of opportunistic infection. Patients also should be asked about recent travel through areas where certain fungi are endemic. A. SYMPTOMS AND SIGNS Common symptoms include headache and lethargy or confusion. Nausea, vomiting, visual loss, seizures, or focal weakness may be noted, while fever may be absent. In a diabetic patient with acidosis, complaints of facial or eye pain, nasal discharge, proptosis, or visual loss should urgently alert the physician to the likelihood of Mucor infection. Careful examination of the skin, orbits, sinuses, and chest may reveal evidence of systemic fungal infection. Neurologic examination may show signs of meningeal irritation, a confusional state, papilledema, visual loss, ptosis, exophthalmos, ocular or other cranial nerve palsies, and focal neurologic abnormalities such as hemiparesis. Because some fungi (eg, Cryptococcus) can cause spinal cord compression, there may be evidence
DISORDERS OF COGNITIVE FUNCTION / 33 Table 1–18. Etiologic agents in fungal meningitis. Name
Geographic Distribution
Opportunistic Infection
Systemic Involvement
Distinctive CSF Findings
Treatment
Cryptococcus Nonspecific neoformans
Sometimes Lungs, skin, bones, (including AIDS) joints
Viscous fluid, positive India ink prep, positive cryptococcal antigen
Amphotericin B + flucytosine (amphotericin B or amphotericin B + fluconazole for AIDS patients)
Coccidioides immitis
Southwestern USA
No
Lungs, skin, bones
Positive complement fixation
Amphotericin B (intravenous and intrathecal), fluconazole, or itraconazole
Candida species
Nonspecific
Yes
Mucous membranes, skin, esophagus, genitourinary tract, heart
Positive Gram stain
Amphotericin B + flucytosine
Aspergillus species
Nonspecific
Yes
Lungs, skin
Polymorphonuclear pleocytosis
Amphotericin B
Mucor species
Nonspecific
Yes, diabetics
Orbits, paranasal sinuses
Amphotericin B + correction of hyperglycemia and acidosis
Histoplasma capsulatum
Eastern and midwestern USA
Sometimes
Lungs, skin, mucous membranes, heart, viscera
Amphotericin B
Blastomyces Mississippi dermatitidis River Valley
No
Lungs, skin, bones, joints, viscera
Amphotericin B
Actinomyces israelii1
Nonspecific
No
Jaw, lungs, abdomen, orbits, sinuses, skin
Sulfur granules, positive Gram stain, AFB smear
Penicillin G or tetracycline
Nocardia species1
Nonspecific
Yes
Lungs, skin
Positive Gram stain, AFB smear
Sulfonamides
1
Actinomyces and Nocardia are filamentous bacteria that are traditionally considered together with fungi.
of spine tenderness, paraparesis, pyramidal signs in the legs, and loss of sensation over the legs and trunk. B. LABORATORY FINDINGS Blood cultures should be obtained. Serum glucose and arterial blood gas levels should be determined in diabetic patients. The urine should be examined for Candida. Chest x-ray may show hilar lymphadenopathy, patchy or miliary infiltrates, cavitation, or pleural effusion. The CT scan or MRI may demonstrate intracerebral mass lesions associated with Cryptococcus (Figure 1–7) or other organisms, a contiguous infectious source in the orbit or paranasal sinuses, or hydrocephalus. CSF pressure may be normal or elevated, and the fluid is usually clear, but may be viscous in the presence of numerous cryptococci. Lymphocytic pleocytosis of
up to 1000 cells/mL is common, but a normal cell count or polymorphonuclear pleocytosis can be seen in early fungal meningitis and normal cell counts are common in immunosuppressed patients. Aspergillus infection typically produces a polymorphonuclear pleocytosis. CSF protein, which may be normal initially, subsequently rises, usually to levels not exceeding 200 mg/dL. Higher levels (<1 g/dL) suggest possible subarachnoid block. Glucose is normal or decreased but rarely below 10 mg/dL. Microscopic examination of Gram-stained and acid-fast smears and India ink preparations may reveal the infecting organism (see Table 1–18). Fungal cultures of CSF and other body fluids and tissues should be obtained, but are often negative. In suspected mucormycosis, biopsy of the affected tissue (usually nasal mucosa) is essential. Useful CSF sero-
34 / CHAPTER 1
T
T
Figure 1–7. T2-weighted MRI in cryptococcal meningitis. Note the bilateral increase in signal in the basal ganglia (arrows) with relative sparing of the thalami (T). This is due to the presence of gelatinous fungal pseudocysts in the territory of the lenticulostriate arteries. (Courtesy of A Gean.)
logic studies include cryptococcal antigen and Coccidioides complement-fixing antibody. Cryptococcal antigen is more sensitive than India ink for detecting Cryptococcus, and should always be looked for in both CSF and serum when that organism is suspected, as in patients with AIDS.
Differential Diagnosis Fungal meningitis may mimic brain abscess and other subacute or chronic meningitides, such as those due to tuberculosis or syphilis. CSF findings and contrast CT scans are useful in differential diagnosis.
Treatment & Prognosis For most organisms causing fungal meningitis, treatment is begun with amphotericin B deoxycholate, 1 mg intravenously as a test dose given over 20–30 minutes, followed the next day by 0.3 mg/kg intravenously in 5% dextrose, given over 2–3 hours. The dose is then increased daily in 5- to 10-mg increments until a maximal dose of 0.5–1.5 mg/kg/d is reached. Treatment is usually continued for 12 weeks.
Nephrotoxicity is common with amphotericin B and may force interruption of therapy for 2–5 days. Newer, lipid-based formulations (eg, amphotericin B lipid complex, amphotericin B cholesteryl sulfate, liposomal amphotericin B) are less nephrotoxic, and can be used in patients who develop such toxicity on amphotericin B deoxycholate. In patients with Coccidioides meningitis or those not responding to intravenous therapy, intrathecal amphotericin B (usually administered via an Ommaya reservoir) is added. The drug is given as a 0.1-mg test dose diluted in 10 mL of CSF, with or without added corticosteroids, and increased to 0.25–0.5 mg every other day. Because administration of amphotericin into the CSF may produce side effects, may require instillation at multiple sites, and may be unsuccessful, another approach is to give fluconazole, 400–600 mg/d, or itraconazole, 200 mg twice daily with meals, by the oral route. In this case, treatment must be continued indefinitely. In cryptococcal meningitis, flucytosine, 100 mg/kg/d orally, added to amphotericin B and given in four divided doses, reduces the duration of therapy from 12 to 6 weeks. The dose of flucytosine must be reduced in renal failure; the major side effect is bone marrow suppression, which is usually reversible. Because of this toxicity, flucytosine is usually omitted when treating cryptococcal meningitis in patients with AIDS. For patients with AIDS and cryptococcal meningitis who do not respond to amphotericin B alone, fluconazole can be added at an initial dose of 400 mg, followed by 200 mg/d, orally or intravenously, for at least 10–12 weeks after CSF cultures are negative. Long-term maintenance therapy with fluconazole, 100–200 mg/d orally, may also reduce the likelihood of recurrence following successful treatment of cryptococcal meningitis in patients with AIDS. Rapid correction of hyperglycemia and acidosis must be combined with amphotericin B treatment and surgical debridement of necrotic tissue in diabetics with mucormycosis. Mortality rates remain high in fungal meningitis. The complications of therapy are frequent, and neurologic residua are common.
PARASITIC INFECTIONS Protozoal and helminthic infections are important causes of central nervous system disease, particularly in immunosuppressed patients (including those with AIDS), and in certain regions of the world (Table 1–19). Rickettsias, the parasitic bacteria that cause Rocky Mountain spotted fever, rarely affect the nervous system. 1. MALARIA Malaria is caused by the protozoan Plasmodium falciparum or another Plasmodium species that is transferred
DISORDERS OF COGNITIVE FUNCTION / 35 Table 1–19. Parasitic infections of the central nervous system. Parasite Protozoa Plasmodium falciparum (malaria)
Epidemiologic and Geographic Factors
Clinical Syndrome
Laboratory Findings
Treatment
Africa, South America, Acute confusional state, Anemia, organisms Southeast Asia, Oceania coma, seizures within red blood cells on peripheral blood smear
Chloroquine (chloroquine sensitive) or quinidine or quinine sulfate (chloroquine resistant)
Toxoplasma gondii
Malignancy or immunosuppression (including AIDS)
Single or multiple focal mass lesions; meningoencephalitis; encephalopathy ± asterixis, myoclonus, or seizures
Positive CT/MRI brain scan; positive SabinFeldman dye test; positive IgM antibody; CSF: normal or lymphocytic pleocytosis, organism on wet mount
Pyrimethamine and sulfadiazine
Naegleria fowleri (primary amebic meningoencephalitis)
Freshwater swimming in southeastern USA
Acute fulminant meningoencephalitis with prominent headache and meningeal signs
CSF: polymorphonuclear pleocytosis, motile organisms on wet mount
Amphotericin B with or without rifampin and chloramphenicol or ketoconazole
Acanthamoeba or Hartmanella species (granulomatous amebic encephalitis)
Chronic illness or immunosuppression
Subacute-chronic meningoencephalitis, often with seizures and focal neurologic signs
CSF: lymphocytic or polymorphonuclear pleocytosis, sluggish organisms on wet mount
None proven
Latin America
Mass lesion or meningoencephalitis, often presenting with headache or seizures
CSF: lymphocytic, pleocytosis, eosinophilia, positive complement fixation or hemagglutination; calcifications on soft tissue x-rays or brain CT scan
Albendazole or praziquantel, corticosteroids, surgical excision of solitary lesion, shunting for hydrocephalus
Hawaii, Asia
Acute-subacute meningitis with headache; stiff neck, vomiting, fever, and paresthesias in about half of patients; selflimited course of 1–2 weeks
Peripheral blood eosinophilia; CSF: eosinophilic and lymphocytic pleocytosis
Mebendazole, levamisole, albendazole, thiabendazole, or ivermectin
Southeastern USA
Acute fever, headache, rash; confusion uncommon
Positive Weil-Felix reaction
Chloramphenicol or doxycycline
Helminths Taenia solium (cysticercosis)
Angiostrongylus cantonensis (eosinophilic meningitis)
Rickettsia Rickettsia rickettsii (Rocky Mountain spotted fever)
36 / CHAPTER 1 to humans by the female Anopheles mosquito. Clinical features include fever, chills, myalgia, nausea and vomiting, anemia, renal failure, hypoglycemia, and pulmonary edema. Although malaria is the most common parasitic infection of humans worldwide, cerebral involvement is rare. Plasmodia reach the central nervous system in infected red blood cells and cause occlusion of cerebral capillaries. Neurologic involvement becomes apparent weeks after infection. In addition to acute confusional states, cerebral malaria can produce seizures and, rarely, focal neurologic abnormalities. The diagnosis is made by finding plasmodia in red blood cells of peripheral blood smears. The CSF may show increased pressure, xanthochromia, mononuclear pleocytosis, or mildly elevated protein.
Prophylaxis Malaria prophylaxis is recommended for travelers to areas where the disease is endemic and consists of chloroquine phosphate, 500 mg orally weekly, beginning 1–2 weeks before travel and continuing until 4 weeks after returning. If exposure to chloroquine-resistant strains is expected, treatment options include mefloquine (250 mg orally weekly for 4 weeks, beginning 1–2 weeks before travel and continuing until 4 weeks after returning), doxycycline (100 mg orally daily, beginning 1–2 days before travel and continuing until 4 weeks after returning), or atovaquone/proguanil (250/100 mg orally daily, beginning 1–2 days before travel and continuing until 1 week after returning).
2. TOXOPLASMOSIS Toxoplasmosis results from ingestion of Toxoplasma gondii cysts in raw meat or cat excrement and is usually asymptomatic. Symptomatic infection is associated with underlying malignancy (especially Hodgkin disease), immunosuppressive therapy, or AIDS.
Clinical Findings Systemic manifestations include skin rash, lymphadenopathy, myalgias, arthralgias, carditis, pneumonitis, and splenomegaly. Central nervous system involvement can take several forms (see Table 1–19). The CSF may be normal, or it may show mild mononuclear cell pleocytosis or slight protein elevation. MRI is superior to CT scanning for demonstrating cerebral toxoplasmosis, and typically shows ring-enhancing lesions (Figure 1–8). The diagnosis is made by blood tests demonstrating a high (≥1:32,000) or rising Sabin-Feldman dye test titer or IgM antibodies to Toxoplasma by indirect immunofluorescence. Accurate diagnosis requires appropriate serologic studies in the immunosuppressed patient who develops neurologic symptoms.
Treatment Chloroquine-sensitive cerebral malaria is treated with chloroquine, 10 mg base/kg by continuous intravenous infusion over 8 hours followed by 15 mg base/kg over 24 hours, or 3.5 mg base/kg by the intramuscular or subcutaneous route every 6 hours to a cumulative dose of ∼25 mg base/kg. Chloroquine-resistant cerebral malaria is treated with quinidine, 10 mg base/kg by intravenous infusion over 1 hour followed by 0.02 mg base/kg/min, or with quinine dihydrochloride (not available in the United States), 20 mg/kg by intravenous infusion over 4 hours followed by 10 mg/kg infused over 2–8 hours every 8 hours. Each of these regimens is continued until oral therapy with chloroquine, amodiaquine, or sulfadoxine and pyrimethamine (for chloroquine-sensitive malaria) or with mefloquine, quinine, or quinidine (for chloroquine-resistant malaria) can be substituted. Cerebral edema is not a consistent finding in cerebral malaria, and corticosteroids are not helpful and may be deleterious. The mortality rate in cerebral malaria is 20–50% and reaches 80% in cases complicated by coma and seizures.
Figure 1–8. T1-weighted, gadolinium-enhanced MRI in cerebral toxoplasmosis complicating HIV infection. Note the multiple ring-enhanced lesions (arrows) with surrounding edema. (Courtesy of A Gean.)
DISORDERS OF COGNITIVE FUNCTION / 37
Treatment Treatment is with pyrimethamine, 25–100 mg/d orally and sulfadiazine, 1–1.5 g orally four times daily, and is continued for 3–4 weeks in immunocompetent patients and for at least several months in immunodeficient patients. Clindamycin, 600 mg orally four times a day, may be substituted for sulfonamides in patients who develop drug sensitivity rashes. Folinic acid (leucovorin), 10 mg orally daily, is added to prevent pyrimethamine-induced leukopenia and thrombocytopenia. 3. PRIMARY AMEBIC MENINGOENCEPHALITIS The free-living ameba Naegleria fowleri causes primary amebic meningoencephalitis in previously healthy young patients exposed to polluted water. Amebas gain entry to the central nervous system through the cribriform plate, producing a diffuse meningoencephalitis that affects the base of the frontal lobes and posterior fossa. It is characterized by headache, fever, nausea and vomiting, signs of meningeal irritation, and disordered mental status. The CSF shows a polymorphonuclear pleocytosis with elevated protein and low glucose; highly motile, refractile trophozoites can be seen on wet mounts of centrifuged CSF. The disease is usually fatal within 1 week, although treatment with amphotericin B, 1 mg/kg/d intravenously, may be effective, as may a combination of amphotericin B, rifampin, and chloramphenicol or ketoconazole.
manifestations of cysticercosis result from the mass effect of intraparenchymal cysts, obstruction of CSF flow by intraventricular cysts, or inflammation that causes basilar meningitis. They include seizures, headache, focal neurologic signs, hydrocephalus, myelopathy, and subacute meningitis. Peripheral blood eosinophilia, soft tissue calcifications, or parasites in the stool suggest the diagnosis. The CSF typically shows a lymphocytic pleocytosis (<100 cells/mL), with eosinophils usually present. Opening pressure is often increased but may be decreased with spinal subarachnoid block; if this is suspected, myelography should be performed. Protein is increased to 50–100 mg/dL, and glucose is 20–50 mg/dL in most cases. Complement fixation and hemagglutination studies can assist in the diagnosis. The CT scan or MRI may show contrast-enhanced mass lesions with surrounding edema, intracerebral calcifications, or ventricular enlargement (Figure 1–9). The indications for treatment of cerebral cysticercosis are controversial. However, patients with symptomatic neurologic involvement (usually seizures) and either meningitis or one or more noncalcified intraparenchymal cysts should be treated. Intraventricular, subarachnoid, and racemose cysts respond poorly to treatment, and calcified cysts do not require treatment. Albendazole, 15 mg/kg/d in three doses taken with meals, and continued for 8 days, is the preferred therapy. Praziquantel, 50 mg/kg/d in three divided
4. GRANULOMATOUS AMEBIC ENCEPHALITIS Granulomatous amebic encephalitis results from infection with Acanthamoeba/Hartmanella species and commonly occurs with chronic illness or immunosuppression. The disorder typically lasts for from 1 week to 3 months and is characterized by subacute or chronic meningitis and granulomatous encephalitis. The cerebellum, brainstem, basal ganglia, and cerebral hemispheres are affected. An acute confusional state is the most common clinical finding. Fever, headache, and meningeal signs each occur in only about half of patients. Seizures, hemiparesis cranial nerve palsies, cerebellar ataxia, and aphasia may occur. Pleocytosis may be primarily lymphocytic or polymorphonuclear; protein is elevated, and glucose is low or normal. Sluggishly motile trophozoites may be seen on wet mounts. Successful treatment has not been reported. 5. CYSTICERCOSIS Cysticercosis is common in Mexico, Central and South America, western and southern Africa, India, China, and southeast Asia. The disease follows ingestion of larvae of the pork tapeworm (Taenia solium) and affects the brain in 60–90% of cases. Larvae undergo hematogenous dissemination, forming cysts in the brain, ventricles, and subarachnoid space. Neurologic
Figure 1–9. Contrast-enhanced CT scan in cerebral cysticercosis. Note the multiple bilateral, small, rounded areas of high density, which represent intraparenchymal cysts. (Courtesy of A Gean.)
38 / CHAPTER 1 doses, can also be used, but blood levels are reduced by anticonvulsants and corticosteroids, which are often also required in these patients. Patients with seizures should also receive anticonvulsants. Corticosteroids are indicated for increased intracranial pressure or lesions near the cerebral aqueduct or intraventricular foramina; these may progress to cause obstructive hydrocephalus. Single accessible intraparenchymal lesions can be removed surgically, and shunting is required for intraventricular lesions causing hydrocephalus.
and a characteristic rash that involves the palms and soles and spreads centrally. Neurologic involvement, which is uncommon, produces a confusional state and, less often, coma or focal neurologic abnormalities. The CSF is normal or shows a mild mononuclear pleocytosis. Treatment is with chloramphenicol, 25–50 mg/kg/d orally or intravenously in four divided doses, or doxycycline, 200 mg/d orally or intravenously, and is continued for 7 days. Neurologic residua may occur.
6. ANGIOSTRONGYLUS CANTONENSIS MENINGITIS Angiostrongylus cantonensis is endemic to southeast Asia and to Hawaii and other Pacific islands. Infection is transmitted by ingestion of infected raw mollusks and produces meningitis with CSF eosinophilia (Table 1–20). Most patients complain of headache, and about half report stiff neck, vomiting, fever, and paresthesias. Most patients have a CSF leukocytosis of 150–1500/mL, mild elevation of protein, and normal glucose. The acute illness usually resolves spontaneously in 1–2 weeks, although paresthesias may persist longer. Levamisole, albendazole, thiabendazole, mebendazole, and ivermectin have been used for treatment; mebendazole 100 mg twice daily orally for 5 days may be preferable. Analgesics, corticosteroids, and reduction of CSF pressure by repeated lumbar punctures may be of value.
LEPTOMENINGEAL METASTASES
7. ROCKY MOUNTAIN SPOTTED FEVER Rocky Mountain spotted fever is caused by Rickettsia rickettsii, an intracellular parasite transmitted to humans by tick bites. R rickettsii damages endothelial cells, leading to vasculitis, microinfarcts, and petechial hemorrhage. Initial symptoms include fever, headache,
Table 1–20. Causes of CSF eosinophilia. Common causes Taenia solium (cysticercosis) Angiostrongylus cantonensis (eosinophilic meningitis) Uncommon causes Other helminthic infections Coccidioides immitis meningitis Hematologic malignancies with meningeal infiltration Foreign matter (including myelography dye) in subarachnoid space Possible causes (less well documented) Neurosyphilis Tuberculous meningitis Nonhematologic malignancies with meningeal infiltration Lymphocytic choriomeningitis Polyarteritis nodosa Allergic reactions
Diffuse metastatic seeding of the leptomeninges may complicate systemic cancer (especially acute lymphocytic leukemia, non-Hodgkin lymphoma, melanoma, acute myelogenous leukemia, carcinoma of the breast, Hodgkin lymphoma, carcinoma of the lung, carcinoma of the gastrointestinal tract, and sarcoma), producing neurologic syndromes with prominent cognitive dysfunction. Primary brain tumors may be associated with meningeal gliomatosis, and medulloblastomas and pineal tumors have a particular propensity for meningeal dissemination. Neoplastic meningitis usually occurs from 3 months to 5 years after the diagnosis of cancer, but may be the presenting manifestation or occur after many years of illness—sometimes in apparently cured patients. Its most frequent symptoms are headache and cognitive disorders, including lethargy, confusion, and memory impairment. Nausea, vomiting, seizures, and gait abnormalities are also common.
Clinical Findings A. SYMPTOMS AND SIGNS Abnormal neurologic signs are often more striking than the symptoms and usually suggest involvement at multiple levels of the neuraxis. The symptoms and signs most often seen when the patient presents with leptomeningeal metastases are listed in Table 1–21. B. LABORATORY FINDINGS The most useful diagnostic procedure is lumbar puncture, which may show increased opening pressure, pleocytosis and elevated protein, and markedly decreased or even immeasurably low glucose (see Table 1–21). Neoplastic meningitis is diagnosed by finding malignant cells in the CSF; large volumes of fluid and repeated lumbar punctures increase the yield of cytologic studies. Several biochemical markers for leptomeningeal metastases can be identified in CSF. These include carcinoembryonic antigen, human chorionic gonadotropin, and α-fetoprotein, which are specific for leptomeningeal metastases, as well as β2-microglobulin, β-glucuronidase, and lactic dehydrogenase isozyme V, which also can be elevated in inflammatory disorders.
DISORDERS OF COGNITIVE FUNCTION / 39 Table 1–21. Presenting symptoms, signs, and CSF findings with leptomeningeal metastases. Feature Symptoms Gait disturbance
Percentage of Patients
Differential Diagnosis 46
Headache
38
Altered mentation
25
Weakness
22
Back pain
18
Nausea or vomiting
12
Radicular pain
12
Paresthesias
10
Signs Lower motor neuron weakness
78
Treatment & Prognosis Untreated, leptomeningeal metastases are typically associated with death within about 2 months. Leptomeningeal leukemia and lymphoma can be successfully treated with radiation and chemotherapy, and some patients with breast cancer or small-cell lung cancer also respond to these approaches. However, even with treatment, most patients with leptomeningeal metastases from solid tumors live only a few months.
60
Cognitive disturbance
50
Extensor plantar response
50
SEPSIS
Dermatomal sensory deficit
50
Ophthalmoplegia
30
Facial weakness
25
Hearing loss
20
Neck meningeal signs
16
Seizures
14
Papilledema
12
Systemic sepsis can produce an encephalopathy that may be related to impaired cerebral blood flow, disruption of the blood-brain barrier, or cerebral edema. Gram-negative infections are the most common cause. Clinical findings include bacteremia and often liver or kidney failure. The EEG is often abnormal. Therapy involves supportive measures, such as assisted ventilation, and treatment of the underlying infection. Mortality is high, but can be prevented by prompt diagnosis and treatment.
Facial sensory deficit
12
Leg meningeal signs
12
VASCULAR DISORDERS HYPERTENSIVE ENCEPHALOPATHY
81
Pleocytosis2
57
Positive cytology
54
Opening pressure elevated3
50
Glucose decreased4
31
Normal
3
>50 mg/dL. >5 white blood cells/mm3. 3 >160 mm CSF. 4 <40 mg/dL. Data from Posner JB: Neurologic Complications of Cancer. Davis, 1997. 2
Neoplastic meningitis can simulate infectious meningitis, metabolic encephalopathy, intraparenchymal or spinal epidural metastasis, remote effects of carcinoma, or chemotherapeutic drug toxicity and may coexist with any of these conditions.
Absent tendon reflex
CSF findings Protein increased1
1
Where clinically indicated, MRI or a metrizamide CT study of the spine, or myelography is performed to exclude the possibility of intraparenchymal metastasis or spinal cord compression by epidural metastasis.
A sudden increase in blood pressure, with or without preexisting chronic hypertension, may result in encephalopathy and headache, which develop over a period of several hours to days. Vomiting, visual disturbances, focal neurologic deficits, and focal or generalized seizures can also occur. Blood pressure in excess of 250/150 mm Hg is usually required to precipitate the syndrome in patients with chronic hypertension; previously normotensive patients may be affected at lower pressures. Coexisting renal failure appears to increase the risk of hypertensive encephalopathy. Cerebrovascular spasm, impaired autoregulation of cerebral blood flow, and intravascular coagulation have all been proposed as the cause of neurological symptoms. These processes can lead to small infarcts and petechial hemorrhages that affect the brainstem most
40 / CHAPTER 1 prominently and other subcortical gray and white matter regions to a lesser extent.
Clinical Findings The physical findings most useful in confirming the diagnosis are those seen on ophthalmoscopy. Retinal arteriolar spasm is almost invariably present. Papilledema, retinal hemorrhages, and exudates are usually present. Lumbar puncture may show normal or elevated CSF pressure and protein. Low-density areas suggestive of edema in the posterior regions of hemispheric white matter are seen on CT scan and corresponding T2 hyperintense areas are seen on MRI (Figure 1–10); the changes are reversible with treatment. Blood studies are important to detect uremia.
Differential Diagnosis Hypertensive encephalopathy is a diagnosis of exclusion. Stroke and subarachnoid hemorrhage also produce encephalopathy with acutely elevated blood pressure, and when focal neurologic abnormalities are present, stroke is by far the most likely diagnosis. Elevated blood pressure, headache, papilledema, and altered consciousness are also seen with intracranial hemorrhage; where this is a consideration, it can be excluded by CT scan or MRI.
Prevention Hypertensive encephalopathy is best prevented by early treatment of uncomplicated hypertension and by prompt recognition of elevated blood pressure in settings—such as acute glomerulonephritis or eclampsia—in which it tends to occur in previously normotensive patients.
Treatment The diagnosis of hypertensive encephalopathy is established when lowering the blood pressure results in rapid resolution of symptoms. This is accomplished with sodium nitroprusside, given by continuous intravenous infusion at an initial rate of 0.5 mg/kg/min, and increased to as much as 3–10 mg/kg/min as required. Alternative approaches include diazoxide, 50–100 mg by intravenous bolus every 5–10 minutes (to a maximum of 600 mg) or 10–30 mg/min by constant intravenous infusion, or labetalol, 20–80 mg by intravenous bolus every 5–10 minutes (to a maximum of 600 mg) or 0.5–2 mg/min by constant intravenous infusion. The patient must be carefully monitored and the infusion rate adjusted to maintain a therapeutic effect without producing hypotension. In the first hour of treatment, mean arterial blood pressure should be reduced by no more than 20–25% and diastolic pressure should not
Figure 1–10. Axial T2-weighted images of the brain of a 39-year-old woman who developed hypertensive encephalopathy in the setting of chronic renal failure. Areas of abnormal high intensity (arrows) represent edema affecting posterior parietal and occipital regions, white matter more than gray. Similar imaging changes can sometimes be seen following generalized seizures and with certain drugs, particularly cyclosporine and chemotherapeutic agents. Imaging abnormalities typically resolve with treatment of the underlying condition. (Courtesy of HA Rowley.)
DISORDERS OF COGNITIVE FUNCTION / 41 be allowed to fall below 100 mm Hg. Treatment should be terminated immediately if neurologic function worsens. Untreated hypertensive encephalopathy can result in stroke, coma, or death but prompt treatment usually produces full clinical recovery.
SUBARACHNOID HEMORRHAGE Subarachnoid hemorrhage must receive early consideration in the differential diagnosis of an acute confusional state. This disorder is discussed in Chapter 2.
VERTEBROBASILAR ISCHEMIA Transient ischemia or stroke in the distribution of the posterior cerebral circulation can produce an acute confusional state. Vertebrobasilar ischemia is discussed in Chapter 9.
RIGHT (NONDOMINANT) HEMISPHERIC INFARCTION Agitated confusion of sudden onset can result from infarction (usually embolic) in the territory of the inferior division of the nondominant (usually right) middle cerebral artery. If the superior division is spared, there is no hemiparesis. Agitation may be so pronounced as to suggest an alcohol withdrawal syndrome, but autonomic hyperactivity is absent. The diagnosis is confirmed by CT brain scan or MRI. Rarely, isolated anterior cerebral artery infarcts or posterior cerebral artery infarcts cause acute confusion.
SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus (SLE) is the most common autoimmune cause of encephalopathy. SLE is nine times more common in women than in men and usually has its onset between the ages of 10 and 40 years. Neurologic involvement is reported in 37–75% of patients. The clinical features that correlate best with nervous system involvement are active mucocutaneous or visceral vasculitis and thrombocytopenia, but clinically active systemic disease need not be present for neurologic symptoms to occur. Neuropathologic findings include fibrinoid degeneration of arterioles and capillaries, microinfarcts, and intracerebral hemorrhages. True vasculitis of cerebral blood vessels is rare.
Clinical Findings A. SYMPTOMS AND SIGNS The most common neurologic features are seizures and an altered mental status. Cognitive disturbances include acute confusional states, schizophreniform psychosis,
depression, and mania. Seizures are usually generalized but may be focal. Less common neurologic manifestations include visual impairment from optic nerve involvement, ptosis, diplopia, hemiparesis, paraparesis, tremor, chorea, cerebellar ataxia, and polyneuropathy. B. LABORATORY FINDINGS Laboratory abnormalities in SLE include antinuclear antibodies, anemia, hypocomplementemia, antinative DNA antibodies, leukopenia, and autoantibodies against ribosomal P proteins. No laboratory finding is diagnostic of nervous system involvement, but CSF shows mild elevation of protein or a modest—usually mononuclear—pleocytosis in about one-third of cases. The EEG frequently shows diffuse slowing or focal abnormalities.
Differential Diagnosis Even in patients with known SLE, encephalopathy can be caused by a variety of factors other than cerebral lupus per se. Coagulopathy, infection, uremia, and emboli from endocarditis must be excluded. A common dilemma is the need to distinguish cerebral lupus from steroid-induced psychosis in patients receiving corticosteroid therapy for SLE. Cerebral lupus is by far the more frequent problem, particularly in patients receiving low or tapering doses of steroids.
Treatment Cerebral lupus is treated with corticosteroids, beginning at 60 mg/d of prednisone or the equivalent. In patients already receiving steroids, the dose should be increased by the equivalent of 5–10 mg/d of prednisone. After symptoms resolve, steroids should be tapered to a low maintenance dose. Seizures are treated with anticonvulsants.
Prognosis Neurologic symptoms of SLE improve in more than 80% of patients treated with corticosteroids, but may also resolve without treatment. Cerebral involvement in SLE has not been shown to adversely affect the overall prognosis.
DISSEMINATED INTRAVASCULAR COAGULATION Disseminated intravascular coagulation (DIC) results from pathologic activation of the coagulation and fibrinolytic systems, usually in the setting of a severe underlying systemic disease. The principal manifestation is hemorrhage. DIC tends to occur at the extremes of age, but patients of any age can be affected. Common findings in the brain include small multifocal infarctions
42 / CHAPTER 1 and petechial hemorrhages involving both gray and white matter. Subdural hematoma, subarachnoid hemorrhage, and hemorrhagic infarction in the distribution of large vessels may also occur.
matter. The antiplatelet drugs ticlopidine and clopidogrel can precipitate TTP, but how this occurs is unclear.
Clinical Findings
A. SYMPTOMS AND SIGNS Patients most often present with altered consciousness, headache, focal neurologic signs, or seizures or with cutaneous hemorrhages in the form of purpura, ecchymoses, or petechiae. Other symptoms include malaise, fatigue, generalized weakness, nausea, vomiting, diarrhea, fever, and abdominal pain. Bleeding from sites other than the skin may occur. Neurologic symptoms may be fleeting and recurrent. The physical examination is helpful in documenting fever, cutaneous hemorrhage, and neurologic dysfunction. TTP usually follows an acute, fulminant course but can be a chronic progressive or remitting and relapsing disorder lasting from months to years. What accounts for the defect in von Willebrand factor-cleaving protease activity in chronic cases is unknown.
Neurologic manifestations are common and include confusional states, coma, focal signs, and seizures. They may precede the definitive hematologic abnormalities of hypofibrinogenemia, thrombocytopenia, fibrin degradation products, and prolonged prothrombin time. Microangiopathic hemolytic anemia may also occur.
Differential Diagnosis Disorders that must be excluded include metabolic encephalopathy, meningoencephalitis, metastatic involvement of the brain or meninges, or stroke caused by nonbacterial thrombotic (marantic) endocarditis. Thrombotic thrombocytopenic purpura (TTP) is distinguished by its tendency to occur in previously healthy patients and its association with normal plasma fibrinogen and normal or only slightly elevated fibrin degradation products.
Treatment Treatment is directed at the underlying disease. Transfusion of red blood cells, platelets, and coagulation factors from fresh-frozen plasma may be indicated. Transfused platelets are often rapidly destroyed, however, and transfused coagulation factors may be converted to anticoagulant fibrin degradation products and worsen the hemorrhagic tendency. Heparin sometimes has been advocated because of its ability to inhibit the coagulation cascade, but its utility is uncertain. Prognosis is related to the severity of the underlying disease.
THROMBOTIC THROMBOCYTOPENIC PURPURA Thrombotic thrombocytopenic purpura (TTP) is a rare multisystem disorder defined by the pentad of thrombocytopenic purpura, microangiopathic hemolytic anemia, neurologic dysfunction, fever, and renal disease. In most cases, the cause is thought to be an IgG-mediated autoimmune reaction against a von Willebrand factorcleaving protease, which allows unusually large multimers of von Willebrand factor to accumulate in the plasma, where they stimulate platelet aggregation. The result is platelet-fibrin thrombus formation with occlusion of small blood vessels, especially at arteriolar-capillary junctions. Pathologic findings in the brain include disseminated microinfarcts and, less frequently, petechial hemorrhages that are present mainly in gray
Clinical Findings
B. LABORATORY FINDINGS Hematologic studies show a Coombs-negative hemolytic anemia with hemoglobin levels usually less than 10 g/dL, normochromic red blood cell indices, fragmented and misshapen erythrocytes, and often nucleated red cells. Platelet counts are less than 20,000/mL in about half the cases and less than 60,000/mL in almost all cases; the white blood cell count is normal or elevated. Coagulation studies are normal or slightly abnormal in most patients: PT and PTT are normal in about 90% of cases and fibrinogen is normal in 80%. Fibrin degradation products are normal in about 50% of cases and slightly elevated in about 25%. Renal involvement may cause hematuria, proteinuria, or azotemia. Spinal fluid is usually normal, but protein may be elevated. Antemortem pathologic diagnosis may be made by gingival biopsy or splenectomy.
Differential Diagnosis DIC is also associated with hemolytic anemia or thrombocytopenia. Idiopathic thrombocytopenic purpura (ITP) is not accompanied by microangiopathic hemolytic anemia or by evidence of multisystem disease. The hemolytic anemias of SLE, autoimmune hemolytic anemia (AIHA), and Evans syndrome (both ITP and AIHA) are Coombs-positive.
Treatment & Prognosis Plasmapheresis is the mainstay of therapy and is sometimes combined with prednisone and antiplatelet agents (aspirin, 325 mg three times daily and dipyridamole, 75 mg three times daily). With treatment, >80% of patients recover, although relapses may occur.
DISORDERS OF COGNITIVE FUNCTION / 43
HEAD TRAUMA Blunt head trauma can produce a confusional state or coma. Acceleration or deceleration forces and physical deformation of the skull can cause shearing of white matter, contusion from contact between the inner surface of the skull and the polar regions of the cerebral hemispheres, torn blood vessels, vasomotor changes, brain edema, and increased intracranial pressure.
CONCUSSION Concussion is characterized by transient loss of consciousness for seconds to minutes without demonstrable structural defects. Unconsciousness is associated with normal pupillary and ocular reflexes, flaccidity, and extensor plantar responses. The return of consciousness is followed by a confusional state that usually lasts from minutes to hours, and is characterized by prominent retrograde and anterograde amnesia (see below). Patients with simple concussion usually recover uneventfully, although headache, dizziness, or mild cognitive impairment may persist for weeks. When unconsciousness is prolonged, delayed in onset after a lucid interval, or associated with focal neurologic abnormalities, the possibility of posttraumatic intracranial hemorrhage should be considered.
INTRACRANIAL HEMORRHAGE Traumatic intracranial hemorrhage can be epidural, subdural, or intracerebral. Epidural hematoma most often results from a lateral skull fracture that lacerates the middle meningeal artery or vein. Patients may or may not lose consciousness initially, but in either event a lucid interval lasting several hours to 1–2 days is followed by the rapid evolution—over hours—of headache, progressive obtundation, hemiparesis, and finally ipsilateral pupillary dilatation from uncal herniation. Death may follow if treatment is delayed. Subdural hematoma after head injury can be acute, subacute, or chronic. In each case, headache and altered consciousness are the principal manifestations. Delay in diagnosis and treatment may lead to a fatal outcome. In contrast to epidural hematoma, the time between trauma and the onset of symptoms is typically longer, the hemorrhage tends to be located over the cerebral convexities, and associated skull fractures are uncommon. Subdural hematoma in the posterior fossa is uncommon. Intracerebral contusion (bruising) or hemorrhage related to head injury is usually located at the frontal or temporal poles. Blood typically enters the CSF, resulting in signs of meningeal irritation and sometimes hydrocephalus. Focal neurologic signs are usually absent or subtle. The diagnosis of posttraumatic intracranial hemor-
rhage is made by CT scan or MRI. Epidural hematoma tends to appear as a biconvex, lens-shaped, extra-axial mass that may cross the midline or the tentorium but not the cranial sutures. Subdural hematoma is typically crescent-shaped and may cross the cranial sutures but not the midline or tentorium. Midline structures may be displaced contralaterally. Epidural and subdural hematomas are treated by surgical evacuation. The decision to use surgery to treat intracerebral hematoma depends upon the clinical course and location. Evacuation, decompression, or shunting for hydrocephalus may be indicated.
SEIZURES POSTICTAL STATE Generalized tonic-clonic (grand mal) seizures are typically followed by a transient confusional state (postictal state) that resolves within 1–2 hours. Disturbances of recent memory and of attention are prominent. When postictal confusion does not clear rapidly, an explanation for the prolonged postictal state must be sought. This occurs in three settings: status epilepticus, an underlying structural brain abnormality (eg, stroke, intracranial hemorrhage), and an underlying diffuse cerebral disorder (eg, dementia, meningitis or encephalitis, metabolic encephalopathy). Patients with an unexplained prolonged postictal state should be evaluated with blood chemistry studies, lumbar puncture, EEG, and CT scan or MRI.
COMPLEX PARTIAL SEIZURES Complex partial (formerly called temporal lobe or psychomotor) seizures produce alterations in consciousness characterized by confusion alone, or by cognitive, affective, psychomotor, or psychosensory symptoms. Complex partial seizures rarely cause diagnostic problems in the patient presenting with an acute confusional state, because spells are typically brief and stereotypical, psychomotor manifestations are often obvious to the observer, and patients themselves may describe classic cognitive, affective, or psychosensory symptoms (see Chapter 8). Complex partial seizures produce a confusional state that may be characterized by a withdrawn or unresponsive state or by agitated behavior. Automatisms such as staring, repetitive chewing, swallowing, lip-smacking, or picking at clothing are characteristic. Complex partial status epilepticus, which is rare, lasts for hours to days. The diagnosis is made or confirmed by EEG.
PSYCHIATRIC DISORDERS Symptoms similar to those associated with acute confusional states—incoherence, agitation, distractibility, hy-
44 / CHAPTER 1 pervigilance, delusions, and hallucinations—also can be seen in a variety of psychiatric disorders. These include psychotic disorders (schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder), mood (depressive and bipolar) disorders, anxiety disorders (posttraumatic stress disorder), and factitious disorders. Such diagnoses may be mistakenly assigned to patients with acute confusional states; conversely, patients with psychiatric disturbances may be thought—incorrectly—to have organic disease. Unlike acute confusional states, psychiatric disorders are rarely acute in onset but typically develop over a period of at least several weeks. The history may reveal previous psychiatric disease or hospitalization or a precipitating psychological stress. Physical examination may show abnormalities related to autonomic overactivity, including tachycardia, tachypnea, and hyperreflexia but no definitive signs of neurologic dysfunction. Routine laboratory studies are normal in the psychiatric disorders listed above, but are useful for excluding organic disorders. Although the mental status examination in acute confusional states is often characterized by disorientation and fluctuating consciousness, patients with psychiatric disorders tend to maintain a consistent degree of cognitive impairment and to be oriented to person, place, and time. Disorientation as to person, especially in the face of preserved orientation in other spheres, is virtually diagnostic of psychiatric disease. Patients with psychiatric disorders exhibit a normal level of consciousness, usually appearing awake and alert, and memory is intact. Disturbances in the content and form of thought (eg, persecutory delusions, delusions of reference, loosening of associations), perceptual abnormalities (eg, auditory hallucinations), and flat or inappropriate affect are common, however. Psychiatric consultation should be sought regarding diagnosis and management.
III. DEMENTIA Dementia is an acquired, generalized, and usually progressive impairment of cognitive function that affects the content, but not the level, of consciousness. Although its incidence increases with advancing age (it has been estimated to affect 5–20% of individuals over age 65), dementia is not an invariable accompaniment of aging. It reflects instead a disorder that affects the cerebral cortex, its subcortical connections, or both. Minor changes in neurologic function, including alterations in memory and other cognitive spheres, can occur with normal aging (Table 1–22). Enlargement of ventricles and cerebral cortical sulci seen on CT or
Table 1–22. Neurologic changes in normal aging. Cognitive Memory loss (benign senescent forgetfulness) Neuroophthalmologic Small, sluggishly reactive pupils Impaired upgaze Impaired convergence Motor Muscular atrophy (intrinsic hand and foot muscles) Increased muscle tone Flexion (stooped) posture Gait disorders (small-stepped or broad-based gait) Sensory Impaired vision Impaired hearing Impaired taste Impaired olfaction Decreased vibration sense Reflexes Primitive reflexes Absent abdominal reflexes Absent ankle jerks
MRI scans (Figure 1–11) is also common with normal aging. These findings should not by themselves be considered indicative of dementia.
APPROACH TO DIAGNOSIS The first step in evaluating a patient with a disorder of cognitive function is to classify the disorder as either a disturbance of the level of consciousness (wakefulness or arousal), such as an acute confusional state or coma, or a disturbance of the content of consciousness, in which wakefulness is preserved. The latter category includes both global cognitive disorders (dementia) and more circumscribed deficits, such as aphasia and amnestic syndromes. This distinction is important because the initial classification of the disorder determines the subsequent diagnostic approach. The most common problem in this area is distinguishing dementia from an acute confusional state, such as that produced by drug intoxication. The clinical features presented in Table 1–1 may be useful in making this distinction. Another common problem is differentiating between dementia and so-called pseudodementia, such as that produced by depression (see below). In the clinical evaluation of patients with suspected dementia, it is important to try to find the cause, even though only about 10% of dementias are reversible. The possibility of reversing or arresting the disorder through appropriate treatment and dramatically improving the quality and duration of life justifies a thor-
DISORDERS OF COGNITIVE FUNCTION / 45
A
B
Figure 1–11. CT scan in cerebrocortical atrophy, showing ventricular dilation (A) and prominent cortical sulci (B). ough diagnostic investigation. A diagnosis is important in other cases for purposes of providing a prognosis and genetic counseling, or alerting family members and medical personnel to the risk of a transmissible disease. As better treatments are developed for dementing disorders that are unresponsive or poorly responsive to current therapy, the importance of arriving at an etiologic diagnosis of dementia will continue to increase.
History Because dementia implies deterioration in cognitive ability, it is important to establish that the patient’s level of functioning has declined. Data that can help to establish the cause of dementia include the time course of deterioration; associated symptoms such as headache, gait disturbance, or incontinence; family history of a similar condition; concurrent medical illnesses; and the use of alcohol and prescribed or unprescribed drugs.
General Physical Examination The general physical examination can contribute to the etiologic diagnosis when it reveals signs of a systemic disease responsible for the dementia. Particularly helpful signs are listed in Table 1–3.
Mental Status Examination The mental status examination helps to determine whether it is the level or the content of consciousness that is impaired and whether the cognitive dysfunction is global or circumscribed. A disorder of the level of consciousness is suggested by sleepiness, inattention, impairment of immediate recall, or disorientation as to place or time. Abnormalities in these areas are unusual in dementia until the disorder is far advanced. To determine the scope of the cognitive dysfunction (global or circumscribed), various spheres of cognition are tested in turn. These include memory, language, parietal lobe functions (pictorial construction, right-left discrimination, localization of objects in space), and frontal lobe or diffuse cerebral cortical functions (judgment, abstraction, thought content, the ability to perform previously learned acts). Multiple areas of cognitive function are impaired in dementia. The Minimental Status Examination (see Table 1–5) provides a useful bedside screening test when dementia is suspected.
Neurologic Examination Certain disorders that produce dementia also affect vision, coordination, or motor or sensory function. De-
46 / CHAPTER 1 tecting such associated neurologic abnormalities can help to establish an etiologic diagnosis. Neurologic signs suggesting causes of dementia are listed in Table 1–3.
mentias), such as depression. Drug intoxication, commonly cited as a cause of dementia in the elderly, actually produces an acute confusional state, rather than dementia.
Laboratory Investigations Laboratory studies that can help to identify the cause of dementia are listed in Table 1–7.
CEREBRAL DISORDERS WITHOUT EXTRAPYRAMIDAL FEATURES
DIFFERENTIAL DIAGNOSIS Common Causes of Dementia
ALZHEIMER DISEASE
Although a wide variety of diseases can produce dementia (Table 1–23), it is generally agreed that Alzheimer disease is the most common cause. Dementia with Lewy bodies, which has been recognized as a distinct entity rather than simply concurrent Alzheimer disease and Parkinson disease, may be second in frequency. Vascular dementia, sometimes referred to as multiinfarct dementia, is the next most common. Other causes of dementia, including reversible dementias, are comparatively rare.
Reversible Causes of Dementia Reversible causes of dementia—such as normal pressure hydrocephalus, intracranial mass lesions, vitamin B12 deficiency, hypothyroidism, and neurosyphilis—are rare. They are important disorders to diagnose promptly, however, because treatment can arrest or reverse the intellectual decline.
Other Important Causes of Dementia Diagnosing dementia caused by Huntington disease allows patients with this disorder (and their families) to benefit from genetic counseling. If Creutzfeldt-Jakob disease or AIDS dementia complex is diagnosed, precautions can be instituted against transmission; the course of AIDS dementia complex may also be modified by antiviral treatment. Progressive multifocal leukoencephalopathy may indicate underlying immunosuppression from HIV infection, lymphoma, leukemia, or another disorder.
Controversial Causes of Dementia Some disorders to which dementia is often attributed may not directly cause the disorder. For example, the existence of a primary alcoholic dementia is questionable, since dementia in alcoholic patients may be the result of related problems such as head trauma or nutritional deficiency.
Pseudodementias About 15% of patients referred for evaluation of possible dementia instead have other disorders (pseudode-
Alzheimer disease is the most common cause of dementia. Its incidence rises from less than 1% per year to more than 7% per year, and its prevalence from 3% to almost 50%, between the ages of 65 and 85 years. This translates into a prevalence of 10–20 million cases worldwide. Men and women are affected with equal frequency, when adjusted for age. Alzheimer disease is a progressive, degenerative disorder of uncertain cause, although abnormal metabolism and deposition of β-amyloid protein appears to be closely linked to pathogenesis (see below). The disease is defined by characteristic histopathologic features, especially neurofibrillary tangles and neuritic (senile) plaques. Neuritic plaques are extracellular deposits that contain the proteins β-amyloid, presenilin 1, presenilin 2, α1-antichymotrypsin, apolipoprotein E, α2-macroglobulin, and ubiquitin. Neurofibrillary tangles are intracellular deposits containing hyperphosphorylated tau (a microtubule-associated protein) and ubiquitin.
Pathogenesis A. GENETICS Alzheimer disease is usually sporadic, but a genetic basis can be identified in about 5% of cases (Table 1–24). Patients with trisomy 21 (Down syndrome) have a high incidence of Alzheimer disease beginning in the fourth decade. Familial Alzheimer disease with autosomal dominant inheritance is genetically heterogeneous. In some families there are mutations in the gene for amyloid precursor protein (APP) on chromosome 21. In other kindreds, familial Alzheimer disease has an especially early onset and more virulent course and is linked to mutations in the gene for presenilin 1, a transmembrane protein, on chromosome 14. Mutations in another transmembrane protein, presenilin 2, have been associated with familial Alzheimer disease in a German kindred. Some cases of familial Alzheimer disease are not caused by these defects, and mutations at other sites are presumed responsible. Genetic factors may also modify susceptibility to Alzheimer disease without being directly causal. In lateonset familial (and to a lesser extent sporadic)
Table 1–23. Causes of dementia. Disorder Cerebral disorders Without extrapyramidal features Alzheimer disease
Distinctive Features
Prominent memory loss, language impairment, visuospatial disturbance, depression, anxiety, delusions
Pick disease
Apathy, disinhibition, anosognosia, logorrhea, echolalia, palilalia
Creutzfeldt-Jakob disease
Myoclonus, ataxia, periodic EEG complexes
Normal-pressure hydrocephalus
Incontinence, gait disorder
With extrapyramidal features Dementia with Lewy bodies (includes diffuse Lewy-body disease and Lewy-body variant of Alzheimer disease)
Fluctuating cognitive function, visual hallucinations, parkinsonism
Corticobasal ganglionic degeneration
Parkinsonism, apraxia (including orofacial apraxia that can mimic aphasia), cortical sensory loss, alien-hand syndrome)
Huntington disease
Chorea, psychosis
Progressive supranuclear palsy
Supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia in extension
Systemic disorders Cancer Brain tumor Meningeal neoplasia
Infection AIDS
Headache, focal neurologic signs, papilledema Focal weakness or sensory deficit, areflexia, pyramidal signs, headache Opportunistic infections, memory loss, psychomotor retardation, ataxia, pyramidal signs, white matter lesions on MRI brain scan
Neurosyphilis
Reactive CSF VDRL, psychosis, Argyll-Robertson pupils, facial tremor, strokes, tabes dorsalis
Progressive multifocal leukoencephalopathy
Visual disturbances, white matter lesions on MRI brain scan
Metabolic disorders Alcoholism
Prominent memory loss, nystagmus, gait ataxia
Hypothyroidism
Myxedema, hair loss, skin changes, hypothermia, headache, hearing loss, tinnitus, vertigo, ataxia, delayed relaxation of tendon reflexes
Vitamin B12 deficiency
Macrocytic anemia, low serum vitamin B12 level, psychosis, sensory disturbance, spastic paraparesis
Organ failure Dialysis dementia
Dysarthria, myoclonus, seizures
Non-Wilsonian hepatocerebral degeneration
Cirrhosis, esophageal varices, fluctuating mental status, dysarthria, pyramidal and extrapyramidal signs, ataxia
Wilson disease
Cirrhosis, dysarthria, pyramidal and extrapyramidal signs, ataxia, Kayser-Fleischer pigmented corneal rings, decreased serum ceruloplasmin
Trauma
Headache, variable pyramidal and extrapyramidal signs
Vascular disorders Chronic subdural hematoma
Headache, hemiparesis, extraaxial collection on CT or MRI brain scan
Vascular dementia
Pseudodementia Depression
Hypertension, diabetes, stepwise progression of deficits, hemiparesis, aphasia, infarcts on CT or MRI brain scan Depressed mood, anhedonia, anorexia, weight loss, insomnia or hypersomnia, suicidality
48 / CHAPTER 1 Table 1–24. Genes implicated in Alzheimer’s disease. Gene
Gene Locus
Protein
Genotype
APP
21q21.3-q22.05
Amyloid β A4 precursor protein
Various missense mutations
Familial Alzheimer disease (autosomal dominant)
PS1
14q24.3
Presenilin 1 (PS1)
Various missense mutations
Familial Alzheimer disease (autosomal dominant) with early onset (age 35–55)
PS2
1q31-q42
Presenilin 2 (PS2)
Various missense mutations
Familial Alzheimer disease (autosomal dominant) in Volga Germans
APOE
19q13.2
Apolipoprotein E
APOE4 polymorphism
Increased susceptibility to Alzheimer disease
Multiple
21
Unknown
Trisomy 21 or chromosome 21-to-14 or 21-to-21 translocation
Down syndrome (early-onset Alzheimer disease)
Alzheimer disease, the risk of being affected and the age at onset are related to the number of apolipoprotein E ε-4 (APOE4) alleles on chromosome 19. How the APOE4 allele (or the absence of other APOE alleles) confers disease susceptibility is unclear. It has been speculated that apolipoprotein E produced by astrocytes may be taken up into neurons and interact abnormally with microtubule-associated proteins, like tau, to produce paired helical filaments in neurofibrillary tangles. Other proteins that may be involved in pathogenesis include α2-macroglobulin and its receptor, low density lipoprotein-related protein-1. B. β-AMYLOID β-Amyloid is the principal constituent of neuritic plaques and is also deposited in cerebral and meningeal blood vessels in Alzheimer disease. β-Amyloid is a 40–
Phenotype
to 42–amino acid peptide produced by proteolytic cleavage of the transmembrane protein, APP (Figure 1–12). Normal processing of APP involves its cleavage by an enzyme called α-secretase to form the 40–amino acid fragment β-amyloid 1–40, which is secreted and cleared from the brain. In Alzheimer disease, APP is cleaved abnormally. The first cleavage is in the extracellular region of APP by an enzyme called β-secretase, which has been identified as the transmembrane protease BACE (β-site APP cleaving enzyme). Then γ-secretase acts within the transmembrane region to generate the abnormal β-amyloid 1–42, which is secreted and accumulates in extracellular plaques. Presenilin 1 and 2 appear to be involved in this latter cleavage step. β-Amyloid, especially in its aggregated form, can be toxic to neurons under some circumstances. It therefore
Aβ
Extracellular
γ -secretase
β -secretase
Intracellular Presenilin
BACE
APP
C99
Figure 1–12. Molecular mechanisms of disease: Proteolytic processing of APP to form β-amyloid. (Adapted from Vassar R, Citron M. Aβ-generating enzymes: recent advances in β- and γ-secretase research. Neuron 2000;27:419–422.)
DISORDERS OF COGNITIVE FUNCTION / 49 has been suggested that the abnormal accumulation of β-Amyloid in Alzheimer disease is responsible for the death of selectively vulnerable neurons. However, others have cited the lack of a clear correlation between the extent of amyloid deposition in the brain and the severity of dementia as evidence against the amyloid hypothesis. C. CHOLINERGIC DEFICIENCY Cholinergic neurons are lost and the acetylcholine-synthesizing enzyme choline acetyltransferase is markedly depleted in the cerebral cortex and hippocampus of patients with Alzheimer disease. Degeneration of the nucleus basalis of Meynert (the principal origin of cortical cholinergic innervation) and of the cholinergic septalhippocampal tract may underlie this abnormality. The cholinergic deficiency in Alzheimer disease has led to the therapeutic use of acetylcholinesterase inhibitors, which enhance cholinergic neurotransmission by inhibiting acetylcholine breakdown (see below).
Clinical Findings A. EARLY MANIFESTATIONS Impairment of recent memory is typically the first sign of Alzheimer disease—often noticed only by family members. As the memory disorder progresses, the patient becomes disoriented to time and then to place. Aphasia, anomia, and acalculia may develop, forcing the patient to leave work or give up the management of family finances. The depression apparent in the earlier stages of the disorder may give way to an agitated, restless state. Apraxias and visuospatial disorientation ensue, causing the patient to become lost easily. Primitive reflexes are commonly found. A frontal lobe gait disorder may become apparent, with short, slow, shuffling steps, flexed posture, wide base, and difficulty in initiating walking. B. LATE MANIFESTATIONS In the late stages, previously preserved social graces are lost, and psychiatric symptoms, including psychosis with paranoia, hallucinations, or delusions, may be prominent. Seizures occur in some cases. Examination at this stage may show rigidity and bradykinesia. Rare and usually late features of the disease include myoclonus, incontinence, spasticity, extensor plantar responses, and hemiparesis. Mutism, incontinence, and a bedridden state are terminal manifestations, and death typically occurs from 5 to 10 years after the onset of symptoms.
Investigative Studies Laboratory investigations do not assist in the diagnosis—except to exclude other disorders. The CT scan or MRI often shows cortical atrophy and enlarged ventri-
cles, but such changes may also be seen in elderly nondemented patients. Cognitive testing may be useful in some cases in helping to distinguish between Alzheimer disease and other causes of dementia.
Differential Diagnosis Early Alzheimer disease may resemble depression or pure memory disorders such as the Korsakoff amnestic syndrome (see below). More advanced Alzheimer disease must be distinguished from Lewy body dementia, multiinfarct dementia, Creutzfeldt-Jakob disease, and other dementing disorders (see below).
Treatment No currently available treatment has been shown unequivocally to reverse existing deficits or to arrest disease progression. However, memantine, an NMDAtype glutamate receptor antagonist drug, may produce modest improvement in patients with moderate or severe Alzheimer disease. Because cholinergic neuronal pathways degenerate and choline acetyltransferase is depleted in the brains of patients with Alzheimer disease, cholinergic replacement therapy has been used in an effort at symptomatic treatment of cognitive dysfunction (Table 1–25). The acetylcholinesterase inhibitors tacrine, donepezil, rivastigmine, galantamine, physostigmine, metrifonate, and eptastigmine have all been shown to produce small (∼5%) improvements in tests of cognitive function. Among these drugs, tacrine, donepezil, rivastigmine, and galantamine are available in the United States. Side effects include nausea, vomiting, diarrhea, and dizziness; tacrine also elevates serum transaminase levels. The better side-effect profile of donepezil and its once-daily dosage schedule have made it the agent of choice. Experimental treatments under investigation include vaccines directed against β-amyloid and the metal chelator, clioquinol. Several drugs also have been tested for their ability to delay the progression of Alzheimer disease, including α-tocopherol, selegiline, idebenone, propentofylline, Gingko biloba, and acetyl-L-carnitine. Of these, only α-tocopherol and selegiline have shown evidence of slight benefit. Antipsychotic drugs, antidepressants, and anxiolytics may be useful in controlling behavioral disturbances associated with Alzheimer disease.
Prognosis Early in the course of the disease, patients can usually remain at home and continue social, recreational, and limited professional activities. Early diagnosis can allow patients time to plan orderly retirement from work, to arrange for management of their finances, and to discuss with physicians and family members the management of future medical problems. Patients in advanced
50 / CHAPTER 1 Table 1–25. Drugs used in the treatment of Alzheimer’s disease. Indication
Drug Class
Cognitive dysfunction
Glutamate antagonist
Memantine (Namenda)
5 mg orally daily, increased by 5 mg each week to 10 mg orally twice daily
Dizziness, headache, constipation, confusion
Acetylcholinesterase inhibitor
Tacrine (Cognex)
10 mg orally four times per day; may be increased to 20 mg orally four times per day after 6 weeks
Abdominal cramps, nausea, vomiting, diarrhea, hepatocellular toxicity (liver enzymes should be monitored twice monthly for 4 months)
Donepezil (Aricept)
5 mg orally at bedtime; may be increased to 10 mg orally at bedtime after 4–6 weeks
Nausea, diarrhea, vomiting, insomnia, fatigue, muscle cramps, anorexia
Rivastigmine (Exelon)
1.5–6 mg orally twice per day
Nausea, vomiting, diarrhea, anorexia
Galantamine (Reminyl)
4–12 mg orally twice per day
Nausea, vomiting, dizziness, diarrhea, anorexia, weight loss
Haloperidol (Haldol)
0.5–2 mg orally at bedtime, or every 4–6 hours
Parkinsonism, akathisia, tardive dyskinesia, increased cognitive dysfunction
Loxapine (Loxitane)
50–250 mg orally daily
Parkinsonism, akathisia, tardive dyskinesia, increased cognitive dysfunction
Risperidone (Risperdal)
2–4 mg orally daily
Parkinsonism, akathisia, tardive dyskinesia, increased cognitive dysfunction
Thioridazine (Mellaril)
25–300 mg orally daily
Parkinsonism, akathisia, tardive dyskinesia, increased cognitive dysfunction
Thiothixene (Navane)
2–20 mg orally daily
Parkinsonism, akathisia, tardive dyskinesia, increased cognitive dysfunction
Citalopram (Celexa)
20–40 mg orally daily
Insomnia, anorexia, ejaculatory failure, nausea, diarrhea
Fluoxetine (Prozac)
5–20 mg orally with breakfast
Insomnia, anorexia, ejaculatory failure, nausea, diarrhea
Paroxetine (Paxil)
5–20 mg orally with breakfast, or in two divided daily doses
Insomnia, anorexia, ejaculatory failure, nausea, diarrhea
Carbamazepine (Tegretol)
400–1200 mg orally in two (extended-release form) or four divided doses
Ataxia
Behavioral disturbance
Antipsychotic
Antidepressant
Anxiolytic
Drug
Dose
Toxicity
Adapted from Mayeux R, Sano M: Treatment of Alzheimer’s disease. N Engl J Med 1999;341:1670–1679.
DISORDERS OF COGNITIVE FUNCTION / 51 stages of the disease may require care in a nursing facility and the use of psychoactive medications. These patients must be protected and prevented from injuring themselves and their families by injudicious actions or decisions. Death from inanition or infection generally occurs 5–10 years after the first symptoms.
FRONTOTEMPORAL DEMENTIA The frontotemporal dementias, including Pick disease, sometimes can be distinguished from Alzheimer disease during life by their generally earlier onset, more prominent behavioral than cognitive dysfunction at presentation, and preferential atrophy of the frontal and anterior temporal lobes on CT scan or MRI of the brain. However, definitive diagnosis is usually not possible during life, and relies instead on histopathological features. These include the distinctively circumscribed pattern of lobar atrophy, the presence of Pick cells and Pick inclusion bodies, the absence of amyloid plaque and neurofibrillary tangles characteristic of Alzheimer disease, and inclusions in neurons and glia that contain the microtubule-associated protein, tau. This latter feature accounts for the classification of frontotemporal dementia as a tauopathy. Familial occurrence of frontotemporal dementia has been documented and mapped to chromosome 17 (17q21). There is no treatment.
CREUTZFELDT-JAKOB DISEASE Creutzfeldt-Jakob disease is an invariably fatal transmissible disorder of the central nervous system characterized by rapidly progressive dementia and variable focal involvement of the cerebral cortex, basal ganglia, cerebellum, brainstem, and spinal cord. The annual incidence is about 1:1,000,000 population. The naturally acquired disease occurs in patients 16–82 years of age, with a peak incidence between 60 and 64 years and an equal sex incidence. More than one member of a family is affected in 5–10% of cases. Conjugal cases are rare. Although transmission from humans to animals has been demonstrated experimentally, documented human-to-human transmission (by corneal transplantation, cortical electrode implantation, or administration of human growth hormone) is rare. The infectious agent is present in the brain, spinal cord, eyes, lungs, lymph nodes, kidneys, spleen, liver, and CSF, but not other body fluids.
Pathogenesis A proteinaceous infectious particle (prion) is the etiologic agent. Familial cases, which are uncommon, have been associated with mutations in a form of the prion protein (cellular isoform, or PrPc) that is expressed by normal neurons but whose function is unknown. In
sporadic cases, an abnormal prion protein (scrapie isoform, or PrPSc), which differs from PrPc in its secondary (folding) structure, has been proposed as the infectious agent. In both circumstances, the result is accumulation of abnormal PrPSc prions in brain tissue. To explain the ability of PrPSc prions to replicate in the brain (despite the fact that they contain no detectable nucleic acids), it has been suggested that infectious PrPSc prions induce a conformational change in normally expressed PrPc prions that converts them to the PrPSc form. Prions have also been implicated in diseases of animals and in three other rare human disorders (Table 1–26)—kuru, a dementing disease of Fore-speaking tribes of New Guinea (apparently spread by cannibalism); Gerstmann-Straussler syndrome, a familial disorder characterized by dementia and ataxia; and fatal familial insomnia, which produces disturbances of sleep and of autonomic, motor, and endocrine function.
Clinical Findings The clinical picture may be that of a diffuse central nervous system disorder or of a more localized dysfunction (Table 1–27). Dementia is present in virtually all cases and may begin as a mild global cognitive impairment or a focal cortical disorder such as aphasia, apraxia, or agnosia. Progression to akinetic mutism or coma typically ensues over a period of months. Psychiatric symptoms including anxiety, euphoria, depression, labile affect, delusions, hallucinations, and changes in personality or behavior may be prominent. Aside from cognitive abnormalities, the most frequent clinical manifestations are myoclonus (often induced by a startle), extrapyramidal signs (rigidity,
Table 1–26. Prion diseases. Human diseases Creutzfeldt-Jakob disease (sporadic) Creutzfeldt-Jakob disease (familial) Creutzfeldt-Jakob disease (new variant) Fatal familial insomnia Gerstmann-Straussler-Scheinker disease Kuru Animal diseases Bovine spongiform encephalopathy Feline spongiform encephalopathy Scrapie (sheep and goats) Transmissible mink encephalopathy Wasting disease of deer and elk Transmissible spongiform encephalopathy of captive wild ruminants Adapted from Johnson RT, Gibbs CJ: CreutzfeldtJakob disease and related transmissible spongiform encephalopathies. N Engl
52 / CHAPTER 1 Table 1–27. Clinical features of sporadic Creutzfeldt-Jakob disease. Feature Cognitive Memory loss Behavioral abnormalities Other Motor Myoclonus Cerebellar ataxia Pyramidal signs Extrapyramidal signs Lower motor neuron signs Visual disturbances Periodic EEG complexes
Percentage 100 57 73 78 71 62 56 12 42 60
Data from Brown P et al: Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994;35:513.
bradykinesia, tremor, dystonia, chorea, or athetosis), cerebellar signs, and extrapyramidal signs. Visual field defects, cranial nerve palsies, and seizures occur less often. A distinct variant of Creutzfeldt-Jakob disease is thought to result from the transmission of bovine spongiform encephalopathy (“mad cow disease”) to humans. This variant is characterized by earlier onset (mean age, about 30 years), a more prolonged course (greater than 1 year), invariable cerebellar involvement, prominent early psychiatric abnormalities, and diffuse amyloid plaques.
midal signs. Where subcortical involvement is prominent, Parkinson disease, cerebellar degeneration, or progressive supranuclear palsy may be suspected. Striking focal signs raise the possibility of an intracerebral mass lesion. Acute metabolic disorders that produce altered mentation and myoclonus (eg, sedative drug withdrawal) can mimic Creutzfeldt-Jakob disease.
Prognosis No treatment is currently available. The disease is usually relentlessly progressive and, although transient improvement may occur, is invariably fatal. In most sporadic cases, death occurs within 1 year after the onset of symptoms: the mean duration of illness in these patients is 7 months. Depending on the specific mutation present, familial forms of the disease may have similar short or much longer courses.
NORMAL-PRESSURE HYDROCEPHALUS Normal-pressure hydrocephalus, a potentially reversible cause of dementia, is characterized by the clinical triad of dementia, gait apraxia, and incontinence. It may be idiopathic or secondary to conditions that interfere with cerebrospinal fluid absorption, such as meningitis or subarachnoid hemorrhage. The dementia is often mild and insidious in onset, and is typically preceded by gait disorder and incontinence. It is characterized initially by mental slowness and apathy and later by global cognitive dysfunction. Deterioration of memory is common, but aphasia and agnosia are rare.
Pathophysiology
The EEG may show periodic sharp waves or spikes (Figure 1–13), which are absent in the variant form described above. CSF protein may be elevated (≤100 mg/dL) and levels of 14–3–3, a normal brain protein that is also elevated in herpes simplex virus encephalitis, are increased. MRI scans may show hyperintense signals in the basal ganglia on T2-weighted images. Definitive diagnosis is by immunodetection of PrPSc in brain tissue obtained at biopsy or, in familial cases, by detection of mutant forms of PrPc in DNA from lymphocytes.
Normal-pressure hydrocephalus is sometimes called communicating (because the lateral, third, and fourth ventricles remain in communication) or nonobstructive hydrocephalus (because the flow of CSF between the ventricles is not obstructed). It is presumed to be due to impaired CSF absorption from arachnoid granulations in the subarachnoid space over the convexity of the hemispheres (Figure 1–14), eg, from meningeal fibrosis and adhesions following meningitis or subarachnoid hemorrhage. In contrast, noncommunicating or obstructive hydrocephalus is caused by a blockade of CSF circulation within the ventricular system (eg, by an intraventricular cyst or tumor) and is associated with increased CSF pressure and often with headache and papilledema.
Differential Diagnosis
Clinical Findings
A variety of other disorders must be distinguished from Creutzfeld-Jakob disease. Alzheimer disease is often a consideration, especially in patients with a less fulminant course and a paucity of cerebellar and extrapyra-
Normal-pressure hydrocephalus usually develops over a period of weeks to months; a gait disorder is often the initial manifestation. This typically takes the form of gait apraxia, characterized by unsteadiness on standing
Investigative Studies
DISORDERS OF COGNITIVE FUNCTION / 53 and difficulty in initiating walking even though there is no weakness or ataxia. The patient can perform the leg movements associated with walking, bicycling, or kicking a ball and can trace figures with the feet while lying or sitting but is unable to do so when the legs are bearing weight. The patient typically appears to be glued to
the floor, and walking, once under way, is slow and shuffling. Pyramidal signs, including spasticity, hyperreflexia, and extensor plantar responses, are sometimes present. Motor perseveration (the inappropriate repetition of motor activity) and grasp reflexes in the hands and feet may occur. Urinary incontinence is a later de-
Fp2-F4 F4-C4 C4-P4 P4-O2 Fp2-F8 F8-T4 T4-T6
T6-O2 Fp1-F3
F3-C3 C3-P3 P3-O1
Fp1-F7 F7-T3 T3-T5 T5-O1 200 µV
1s
Figure 1–13. Electroencephalogram of a patient with Creutzfeldt-Jakob disease, showing triphasic waves with sharpened outlines; these occur repetitively about once every second.
54 / CHAPTER 1 Choroid plexus of lateral ventricle
Arachnoid granulation
Interventricular foramen of Monro
Choroid plexus of third ventricle
Superior sagittal sinus
Dura mater
Arachnoid Pia mater
Cerebral vein
Subarachnoid space Cerebral aqueduct Choroid plexus of fourth ventricle
Foramen of Magendie
Foramen of Luschka
Figure 1–14. Circulation of cerebrospinal fluid (CSF). CSF is produced by the choroid plexus, which consists of specialized secretory tissue located within the cerebral ventricles. It flows from the lateral and third ventricles through the cerebral aqueduct and fourth ventricle and exits the ventricular system through two laterally situated foramina of Luschka and a single, medially located foramen of Magendie. CSF then enters and circulates through the subarachnoid space surrounding the brain and spinal cord. It is ultimately absorbed through arachnoid granulations into the venous circulation.
velopment, and patients may be unaware of it; fecal incontinence is uncommon.
Investigative Studies Lumbar puncture reveals normal or low opening pressure. The CT scan or MRI typically shows enlarged lateral ventricles without increased prominence of cortical sulci (Figure 1–15). Radionuclide cisternography classi-
cally shows isotope accumulation in the ventricles, delayed clearance, and failure of ascent over the cerebral convexities. This pattern is not necessarily present in patients who respond to shunting, however. Transient improvement in gait, cognitive testing, or sphincteric function following the removal of 30–50 mL of CSF by lumbar puncture is probably the best predictor of a favorable clinical response to shunting (see below).
DISORDERS OF COGNITIVE FUNCTION / 55
Figure 1–15. CT scan at two levels in normal-pressure hydrocephalus, showing enlarged lateral ventricles without enlargement of the cortical sulci.
Differential Diagnosis A variety of conditions that produce dementia must be considered in the differential diagnosis. Alzheimer disease tends to follow a longer course, often with prominent focal cortical dysfunction and enlarged cortical sulci shown in a CT scan or MRI. Parkinsonism may be simulated by the gait disorder but can be distinguished by extrapyramidal rigidity, tremor, and response to antiparkinsonian medications. Vascular dementia should be suspected if the disorder follows a stepwise course, or pseudobulbar palsy, focal sensorimotor signs, or a history of stroke is encountered.
Treatment Some patients, especially those with hydrocephalus from meningitis or subarachnoid hemorrhage, recover or improve following ventriculoatrial, ventriculoperitoneal, or lumboperitoneal shunting. In idiopathic normal-pressure hydrocephalus, about one-half of patients have sustained improvement and about one-third have a good or excellent response (ie, return to work) after shunting. As noted above, a favorable response to the removal of CSF by lumbar puncture may be the best predictor of successful surgery. Complications of shunting occur in about one-third of patients and include shunt infection, subdural hematoma, and shunt malfunction that necessitates replacement.
CEREBRAL DISORDERS WITH EXTRAPYRAMIDAL FEATURES DEMENTIA WITH LEWY BODIES Dementia with Lewy bodies is probably the second most common cause of dementia, as up to one-fourth of elderly demented patients who come to autopsy have round, eosinophilic, intracytoplasmic neuronal inclusions (Lewy bodies) in the cerebral cortex and brainstem. These contain α-synuclein, a protein that is also found in Lewy bodies in Parkinson disease, and tau, which is present in Alzheimer disease and frontotemporal dementia (see above). Dementia with Lewy bodies is found in patients with (Lewy-body variant of Alzheimer disease) and without (diffuse Lewy-body disease) histopathological features of Alzheimer disease, and is probably a heterogeneous disorder. In contrast to Alzheimer disease, it is characterized clinically by cognitive decline without prominent early memory impairment. Other distinctive features include fluctuating cognitive ability, well-formed visual hallucinations, and signs of parkinsonism, especially rigidity and bradykinesia. These patients may respond well to anticholinesterase drugs such as tacrine or donepezil (Table 1–25), but are especially sensitive to extrapyramidal side effects of antipsychotic drugs, which therefore should be avoided or used with caution.
56 / CHAPTER 1
CORTICOBASAL GANGLIONIC DEGENERATION This dementing disorder is also associated with parkinsonism, especially rigidity, bradykinesia, postural instability, and action (but rarely resting) tremor, as well as with a variety of asymmetric cortical motor and sensory defects. These include apraxias affecting the eye movements, speech, and limbs, the latter of which may produce the alien-hand sign, in which the limb moves seemingly of its own accord.
HUNTINGTON DISEASE Huntington disease is an autosomal dominant heredodegenerative condition characterized by a movement disorder, psychiatric symptoms, and dementia. The cause is an expanded CAG trinucleotide repeat coding for a polyglutamine tract in the Huntington gene on chromosome 4 (4p16.3). Dementia, which usually becomes apparent after chorea and psychiatric symptoms have been present for a few years, precedes chorea in about one-fourth of cases. A memory disturbance affecting all aspects of memory is an early and prominent feature; aphasia, apraxia, agnosia, and global cognitive dysfunction tend to occur later. Huntington disease is discussed further in Chapter 7.
PROGRESSIVE SUPRANUCLEAR PALSY Progressive supranuclear palsy is an idiopathic degenerative disorder that primarily affects subcortical gray matter regions of the brain. The classic clinical features are supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia with or without extrapyramidal rigidity of the limbs, and dementia. The disorder of movement is a conspicuous feature of this syndrome, which is discussed further in Chapter 7.
SYSTEMIC DISORDERS CANCER 1. BRAIN TUMOR Brain tumors produce dementia and related syndromes by a combination of local and diffuse effects, including edema, compression of adjacent brain structures, increased intracranial pressure, and impairment of cerebral blood flow. The tumors most likely to produce generalized cerebral syndromes are gliomas arising in the frontal or temporal lobes or the corpus callosum. Although such lesions tend to infiltrate subcortical white matter extensively, they initially give rise to few focal neurologic signs. The dementia associated with brain tumor is charac-
terized by prominent mental slowness, apathy, impaired concentration, and subtle alterations in personality. Depending on the areas of involvement, memory disorder, aphasia, or agnosia may be seen early. Brain tumors ultimately produce headache, seizures, or focal sensorimotor disturbances. Brain tumor is covered in detail in Chapter 2. 2. MENINGEAL NEOPLASIA Meningeal neoplasia, discussed above as a cause of confusional states, may also produce dementia that is commonly associated with headache as well as symptoms and signs of dysfunction at multiple sites in the nervous system. The diagnosis is established by cytologic studies of the CSF.
INFECTION 1. AIDS AIDS dementia complex is the most common neurologic complication of AIDS. Although especially common in severely immunosuppressed patients late in the course of the disease, it can also be an early or presenting manifestation.
Pathogenesis AIDS dementia complex results from invasion of the brain by a retrovirus, human immunodeficiency virus type 1 (HIV-1). The virus appears to reach the central nervous system early in the course of systemic HIV-1 infection; monocytes, macrophages, and microglia are the principal cell types affected. Neurologic involvement at this stage may be asymptomatic, or it can produce transient symptomatic HIV-1 meningitis (see above). The infection then seems to be contained until progressive immunosuppression impairs the normal host defense mechanisms, leading to increased HIV-1 production in the brain and, perhaps, the emergence of neurotropic strains. Productive viral infection within the brain seems to be associated with multinucleated cells. HIV-1 does not appear to replicate within neurons, astrocytes, or oligodendrocytes in vivo, and the loss of these cell types is not prominent in brains of patients with AIDS dementia complex. It has therefore been suggested that neuronal function is impaired by an indirect neurotoxic mechanism. This might involve cytokines released from HIV-infected monocytes or macrophages, viral products such as the HIV-1 envelope protein gp120, or molecules that mimic the effects of excitotoxic amino acids.
Pathology The earliest histopathologic sign is pallor of subcortical and periventricular cerebral white matter associated
DISORDERS OF COGNITIVE FUNCTION / 57 with reactive astrocytosis but few inflammatory changes. More advanced cases are associated with parenchymal and perivascular infiltration by macrophages, microglia, lymphocytes, and multinucleated cells; the last are thought to result from the virus-induced fusion of macrophages. These changes affect the white matter, basal ganglia, thalamus, and pons and are accompanied by reactive astrocytosis. Spongy vacuolation of white matter occurs infrequently. Neuronal loss has been reported. The spinal cord may also be affected by a vacuolar myelopathy (see Chapter 5) resembling that caused by vitamin B12 deficiency.
Clinical Findings The onset is usually insidious and is associated with cognitive and behavioral symptoms, such as forgetfulness, apathy, social withdrawal, and motor symptoms, including impaired balance, leg weakness, and deterioration of handwriting (Table 1–28). Examination at this early stage may also show cerebellar ataxia, pyramidal signs such as hyperreflexia and extensor plantar responses, weakness in one or both legs, postural tremor, and dysarthria. As the disease progresses, hypertonia, fecal and urinary incontinence, primitive reflexes, myoclonus, seizures, quadriparesis, and organic psychosis with delusions and visual hallucinations can occur.
Investigative Studies Antibodies to HIV are detectable in the blood. The CSF is usually abnormal and may show a mild to moderate elevation of protein (≤200 mg/dL), a modest, usually mononuclear pleocytosis (≤50 cells/µL), and oligoclonal bands. CT scans and MRI usually demonstrate cerebrocortical atrophy with ventricular dilation and may also show diffuse involvement of subcortical white matter (Figure 1–16).
Treatment Combination pharmacotherapy of HIV infection can prolong life by inhibiting replication of HIV and improving immune function. The available drugs fall into three classes: nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors. Treatment must be individualized, and continually updated treatment guidelines are available from the United States Department of Health and Human Services website at http://www.aidsinfo.nih.gov/ guidelines/. Preferred therapy for antiretroviral drugnaive, non-pregnant patients includes a nonnucleoside reverse transcriptase inhibitor-based regimen consisting of efavirenz, lamivudine, and either zidovudine, tenofovir DF or stavudine, and a protease inhibitor-based regimen that employs lopinavir/ritonavir (Kaletra), lamivudine, and either zidovudine or stavudine.
Table 1–28. Clinical features of AIDS dementia complex. Feature
Percentage of Patients Early Stage
Symptoms Memory loss Behavioral changes (eg, social withdrawal) Depression Motor symptoms (eg, imbalance, weakness, deteriorated handwriting) Apathy Confusion Hallucinations Signs Cognitive Psychomotor retardation Dementia Psychosis Mutism Motor Ataxia Hypertonia Tremor Paraparesis or quadriparesis Monoparesis or hemiparesis Myoclonus Other Hyperreflexia Primitive reflexes Seizures Incontinence Investigative studies1 CSF Mononuclear pleocytosis Increased protein Decreased glucose Oligoclonal IgG bands Imaging Cerebral cortical atrophy (CT) Cerebral cortical atrophy (MRI) White matter lesions (CT) White matter lesions (MRI)
Late Stage
80 30
74 11
30 20
16 21
15 15 5
58 42 11
61 39 5 0
84 100 16 40
34 22 16 13 5 0
71 44 45 33 2 20
36 22 7 0
78 38 20 47
19 66 1 25 79 55 11 35
1 All stages. Adapted from Navia BA et al: The AIDS dementia complex. 1. Clinical features. 2. Neuropathology. Ann Neurol 1986; 19:517–524 and 525–535, and McArthur JC: Neurologic manifestations of AIDS. Medicine 1987;66:407–437.
58 / CHAPTER 1
Clinical Findings A. EARLY SYPHILIS Syphilis is caused by Treponema pallidum transmitted by sexual contact, which results in infection in about one-third of encounters with infected individuals. Primary syphilis is characterized by local skin lesions (chancres) that usually appear within 1 month of exposure. There are no neurologic symptoms. Hematogenous spread of T pallidum produces symptoms and signs of secondary syphilis within 1–6 months. These include fever, skin rash, alopecia, anogenital skin lesions, and ulceration of mucous membranes; neurologic symptoms are still uncommon at this stage. Meningeal syphilis, the earliest form of symptomatic neurosyphilis, is most often seen 2–12 months after primary infection. Clinical features include headache, stiff neck, nausea and vomiting, and cranial nerve (especially II, VII, or VIII) involvement.
Figure 1–16. T2-weighted MRI in AIDS dementia complex, showing extensive, bilaterally symmetrical increases in signal intensity (arrows) in white matter (centrum semiovale) of the frontal lobes.
Side effects vary, but certain class-specific patterns have been noted. Nucleosides can cause fatal lactic acidosis with hepatic steatosis, nonnucleosides are associated with skin rash (including Stevens-Johnson syndrome with nevirapine), and protease inhibitors may produce gastrointestinal disturbances and increased blood levels of aminotransferases. Neurologic side effects of drugs used to treat HIV include myopathy (zidovudine), neuropathy (stavudine, didanosine, zalcitabine), paresthesias (ritonavir, amprenavir), and nightmares and hallucinations (efavirenz).
Prognosis The course may be steadily progressive, or it can be acutely exacerbated by concurrent pulmonary infection. Patients usually die 1–9 months after the onset of dementia from aspiration or opportunistic infection. 2. NEUROSYPHILIS Neurosyphilis was a common cause of dementia before the widespread use of penicillin permitted effective treatment of early syphilis. Dementia from neurosyphilis is now rare, but the resurgence of syphilis in recent years suggests that it may become more common.
B. MENINGOVASCULAR SYPHILIS This delayed manifestation of neurosyphilis occurs 4–7 years into the course of the disease and usually presents with transient ischemic attacks or stroke (see Chapter 9). C. LATE (PARENCHYMATOUS) NEUROSYPHILIS This produces the syndromes of general paresis and tabes dorsalis, which can occur separately or together (taboparesis); either one can occur in combination with optic atrophy. 1. General paresis—A chronic meningoencephalitis caused by active spirochetal infection, this was the usual cause of dementia and psychiatric disorders related to neurosyphilis in the prepenicillin era. Onset is with gradual memory loss or altered affect, personality, or behavior. This is followed by global intellectual deterioration with grandiosity, depression, psychosis, and focal weakness. Terminal features include incontinence, seizures, or strokes. Neurologic examination may show tremor of the face and tongue, paucity of facial expression, dysarthria, and pyramidal signs. 2. Taboparesis—In taboparesis—the coexistence of tabes dorsalis (see Chapter 6) with general paresis— signs and symptoms include Argyll Robertson pupils (see Chapter 4), lancinating pains, areflexia, posterior column sensory deficits with sensory ataxia and Romberg sign, incontinence, impotence, Charcot (hypertrophic) joints, and genu recurvatum (hyperextended knees). Optic atrophy may also be present.
Investigative Studies Treponemal serologic blood tests (FTA-ABS or MHATP) are reactive in almost all patients with active neurosyphilis, but nontreponemal blood tests (VDRL or RPR) can be negative; therefore, a treponemal blood test should be obtained in all suspected cases. If this is
DISORDERS OF COGNITIVE FUNCTION / 59 nonreactive, neurosyphilis is effectively excluded; if it is reactive, lumbar puncture should be performed to confirm the diagnosis of neurosyphilis and provide a baseline CSF profile against which to gauge the efficacy of subsequent treatment. The CSF in active neurosyphilis shows a lymphocytic pleocytosis and reactive nontreponemal CSF serology in almost all cases. The exceptions are acute syphilitic meningitis and meningovascular syphilis, in which pleocytosis may precede seroconversion so that nontreponemal CSF tests are falsely negative early on, and end-stage tabes dorsalis, in which the CSF can be normal. Other CSF abnormalities include protein elevation, increased γ-globulin, and the presence of oligoclonal bands.
Treatment Neurosyphilis is treated with a 10-day course of aqueous penicillin G, 2–4 × 106 units intravenously every 4 hours. Tetracycline or erythromycin can be used for patients allergic to penicillin. Fever and leukocytosis may occur shortly after therapy is started (Herxheimer reaction) but are transient. Failure of the CSF to return to normal within 6 months requires retreatment. Neither failure of treatment nor relapse is convincingly more common in HIV-1-infected patients.
Prognosis
The CSF is usually normal but may show a mild increase in pressure, white cell count, or protein. The CT scan or MRI shows multifocal white matter abnormalities (Figure 1–17). When the diagnosis is in doubt, it can be established by brain biopsy. The disorder is almost uniformly fatal, and treatment with such antiviral agents as cytosine arabinoside, adenine arabinoside, or amantadine generally has been unsuccessful.
METABOLIC DISORDERS 1. ALCOHOLISM Certain complications of alcoholism can cause dementia. These include acquired hepatocerebral degeneration from alcoholic liver disease, chronic subdural hematoma from head trauma, and nutritional deficiency states. Pellagra, caused by deficiency of nicotinic acid (niacin), affects neurons in the cerebral cortex, basal ganglia, brainstem, cerebellum, and anterior horns of the spinal cord. Systemic involvement is manifested by diarrhea, glossitis, anemia, and erythematous skin lesions. Neurologic involvement may produce dementia; psychosis; confusional states; pyramidal, extrapyramidal, and cerebellar signs; polyneuropathy; and optic neuropathy. Treatment is with nicotinamide, but the neurologic deficits may persist despite treatment.
After penicillin (or other antibiotic) treatment for general paresis, the clinical condition may improve or stabilize; in some cases it continues to deteriorate. Patients with persistent CSF abnormalities or symptomatic progression despite therapy should be retreated. Patients with reactive CSF serological tests but no pleocytosis are unlikely to respond to penicillin therapy but are usually treated nevertheless. 3. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy results from infection with a papovavirus called JC virus. Antibodies are present in most adults, but symptomatic infection is rare. It is most common in patients with AIDS, lymphoma or leukemia, carcinoma, sarcoidosis, tuberculosis, or pharmacologic immunosuppression following organ transplantation, and rare in those with normal immune function. The virus infects oligodendrocytes, leading to diffuse and patchy demyelination that primarily affects white matter of the cerebral hemispheres but also involves the brainstem and cerebellum. The course is subacute and progressive, leading to death in 3–6 months. Fever and systemic symptoms are absent. Dementia and focal cortical dysfunction are prominent. Signs of the latter include hemiparesis, visual deficits, aphasia, dysarthria, and sensory impairment. Ataxia and headache are uncommon and seizures do not occur.
Figure 1–17. T2-weighted MRI in progressive multifocal leukoencephalopathy, showing abnormally high signal intensity (arrows) in white matter of the right parietal and occipital lobes. (Courtesy of A Gean.)
60 / CHAPTER 1 Marchiafava Bignami syndrome is characterized by necrosis of the corpus callosum and subcortical white matter and occurs most often in malnourished alcoholics. The course can be acute, subacute, or chronic. Clinical features include dementia, spasticity, dysarthria, gait disorder, and coma. The diagnosis can sometimes be made by CT scan or MRI. No specific treatment is available, but cessation of drinking and improvement of nutrition are advised. The outcome is variable: patients may die, survive with dementia, or recover. Alcoholic dementia due to direct toxic effects of ethanol on the brain has been proposed to occur, but no distinctive abnormalities have been identified in the brains of demented alcoholics. Dementia in alcoholics is more likely to result from one or more of the metabolic and traumatic disorders mentioned above.
tia supervenes. The EEG shows paroxysmal high-voltage slowing with intermixed spikes and slow waves; these abnormalities can be reversed by diazepam. Aluminum in the dialysate is a major etiologic suspect, and removing trace metals from the dialysate has decreased the syndrome’s incidence. Mean survival is 6 months.
2. HYPOTHYROIDISM Hypothyroidism (myxedema), which is discussed above as a cause of acute confusional states, can also produce a reversible dementia or chronic organic psychosis. The dementia is a global disorder characterized by mental slowness, memory loss, and irritability. Focal cortical deficits do not occur. Psychiatric manifestations are typically prominent and include depression, paranoia, visual and auditory hallucinations, mania, and suicidal behavior. Patients with myxedema may complain of headache, hearing loss, tinnitus, vertigo, weakness, or paresthesia. Examination may show deafness, dysarthria, or cerebellar ataxia. The most suggestive finding is delayed relaxation of the tendon reflexes. Diagnosis and treatment are discussed above. Cognitive dysfunction is usually reversible with treatment.
Systemic manifestations of chronic liver disease are usually present. The neurologic syndrome is fluctuating but progressive over 1–9 years, and may be punctuated by episodes of acute hepatic encephalopathy. Dementia, dysarthria, and cerebellar, extrapyramidal, and pyramidal signs are the most common features. Dementia is marked by mental slowness, apathy, impaired attention and concentration, and memory disturbance. Cerebellar signs include gait and limb ataxia and dysarthria; nystagmus is rare. Extrapyramidal involvement may produce rigidity, resting tremor, dystonia, chorea, or athetosis. Asterixis, myoclonus, hyperreflexia, and extensor plantar responses are common; paraparesis is rare. Laboratory studies show abnormal hepatic blood chemistries and elevated blood ammonia, but the degree of abnormality bears no direct relationship to the severity of neurologic symptoms. The CSF is normal, except for increased glutamine and occasional mild elevation of protein.
3. VITAMIN B12 DEFICIENCY Vitamin B12 deficiency is a rare cause of reversible dementia and organic psychosis. Like the acute confusional state associated with vitamin B12 deficiency (see above), dementia can occur with or without hematologic and other neurologic manifestations. The dementia consists of global cognitive dysfunction with mental slowness, impaired concentration, and memory disturbance; aphasia and other focal cortical disorders do not occur. Psychiatric manifestations are often prominent and include depression, mania, and paranoid psychosis with visual and auditory hallucinations. Laboratory findings and treatment are discussed above.
ORGAN FAILURE 1. DIALYSIS DEMENTIA This rare disorder typically occurs in patients receiving chronic hemodialysis. Clinical features include dysarthria, myoclonus, and seizures. These are initially intermittent, but later become permanent, and demen-
2. NON-WILSONIAN HEPATOCEREBRAL DEGENERATION Acquired (non-Wilsonian) hepatocerebral degeneration is an uncommon complication of chronic hepatic cirrhosis with spontaneous or surgical portosystemic shunting. Symptoms may be related to failure of the liver to detoxify ammonia. Neurologic symptoms precede hepatic symptoms in about one-sixth of patients.
Clinical Findings
Differential Diagnosis Wilson disease can be distinguished by its earlier onset, Kayser-Fleischer rings and abnormal copper metabolism. Alcoholic cerebellar degeneration primarily affects gait and is not accompanied by extrapyramidal or pyramidal signs.
Treatment & Prognosis Patients may benefit from a low-protein diet, lactulose, neomycin, liver transplantation, or portosystemic shunting, and improvement following levodopa or bromocriptine therapy has been described. Death results from progressive liver failure or variceal bleeding. 3. WILSON DISEASE Wilson disease (hepatolenticular degeneration) is a rare but treatable autosomal recessive hereditary disorder of copper metabolism that produces dementia and ex-
DISORDERS OF COGNITIVE FUNCTION / 61 trapyramidal symptoms. The disease results from mutations in the ATP7B gene on chromosome 13 (13q14.3–q21.1), which codes for the β polypeptide of a copper-transporting ATPase. Wilson disease is discussed further in Chapter 7.
TRAUMA Severe open or closed head injury, particularly when followed by prolonged unconsciousness, may cause impaired memory and concentration, personality changes, headache, focal neurologic disorders, or seizures. Cognitive impairment is nonprogressive, and the cause is usually obvious. Delayed, progressive posttraumatic dementia in boxers (dementia pugilistica) is characterized by cheerful or labile affect, mental slowness, memory deficit, and irritability. Associated neurologic abnormalities include tremor, rigidity, bradykinesia, dysarthria, cerebellar ataxia, pyramidal signs, and seizures. Neuroradiologic investigations may show cortical atrophy and cavum septi pellucidi.
VASCULAR DISORDERS 1. CHRONIC SUBDURAL HEMATOMA Chronic subdural hematoma usually affects patients aged 50–70 years, often after minor head trauma. Other risk factors include alcoholism, cerebral atrophy, epilepsy, the use of anticoagulation, ventricular shunts, and long-term hemodialysis. The onset of symptoms may be delayed for months after trauma. Hematomas are bilateral in about one-sixth of cases.
Clinical Findings Headache is the initial symptom in most patients. Confusion, dementia, hemiparesis, and vomiting may ensue. The most frequent signs are cognitive disturbance, hemiparesis, papilledema, and extensor plantar responses. Aphasia, visual field defects, and seizures are uncommon, but can occur. The hematoma can usually be seen on CT scan or MRI (Figure 1–18) as an extraaxial crescent-shaped area of decreased density, with ipsilateral obliteration of cortical sulci and often ventricular compression. The scan should be carefully reviewed for evidence of bilateral subdural collections. Isodense collections may become more apparent after contrast infusion. In a few cases, demonstration of the hematoma may require cerebral arteriography, which should always be undertaken bilaterally.
Treatment Unless contraindicated by medical problems or spontaneous improvement, symptomatic hematomas should be surgically evacuated.
Figure 1–18. CT scan in chronic subdural hematoma, showing bilateral low-density collections between the inner table of the skull and the cerebral hemispheres (arrows).
2. VASCULAR DEMENTIA Vascular dementia is thought to be the third most common cause of dementia, after Alzheimer disease and dementia with Lewy bodies. Most patients with this diagnosis have either multiple large cortical infarcts from occlusion of major cerebral arteries or several smaller infarcts (lacunar state; see Chapter 9) affecting subcortical white matter, basal ganglia, or thalamus. The relationship between cerebral vascular disease and dementia is poorly characterized. For example, the number of strokes, their locations, and the total infarct volume required for strokes to produce dementia are uncertain, making it often difficult to determine if strokes are the cause of dementia in a given patient. Whether dementia can result from cerebrovascular disease without frank infarction, as is commonly presumed to exist when periventricular white matter lesions are detected by neuroimaging, is also controversial. Thus, the absence of neuroradiologic signs of cerebrovascular disease argues strongly against a vascular basis for dementia, but the presence of vascular lesions does not prove that they are causal. This is especially true when another cause of dementia, such as Alzheimer disease, coexists with cerebrovascular disease.
62 / CHAPTER 1
Clinical Findings As classically described, patients with multiinfarct dementia have a history of hypertension, a stepwise progression of deficits, a more or less abrupt onset of dementia, and focal neurologic symptoms or signs. Because extensive pathologic changes may already exist at presentation, it is assumed that patients can remain functionally well compensated until a new and perhaps otherwise innocuous infarct tips the balance. The neurologic examination commonly shows pseudobulbar palsy with dysarthria, dysphagia, and pathologic emotionality (pseudobulbar affect), focal motor and sensory deficits, ataxia, gait apraxia, hyperreflexia, and extensor plantar responses.
Investigative Studies The MRI (Figure 1–19) may show multiple small subcortical lucencies. Extensive areas of low density in subcortical white matter are seen in Binswanger disease (subcortical arteriosclerotic encephalopathy), which may be a related condition. MRI is more sensitive than CT for detecting these abnormalities. Additional laboratory studies should be performed to exclude cardiac emboli, polycythemia, thrombocyto-
sis, cerebral vasculitis, and meningovascular syphilis as causes of multiple infarctions, particularly in younger patients or those without a history of hypertension.
Treatment Hypertension, when present, should be treated to reduce the incidence of subsequent infarction and to prevent other end-organ diseases. Antiplatelet agents (discussed in Chapter 9) may help to reduce the risk of future strokes.
PSEUDODEMENTIA Depression is the disorder most commonly mistaken for dementia. Because depression is common and treatable, distinguishing between the two conditions is important. Both dementia and depression can be characterized by mental slowness, apathy, self-neglect, withdrawal, irritability, difficulty with memory and concentration, and changes in behavior and personality. In addition, depression can be a feature of dementing illnesses, and the two frequently coexist. Clinical features that help in the differentiation are listed in Table 1–29. When depression is being considered, psychiatric consultation should be obtained. If depression is identified as a significant problem and is not correctable by treatment of an underlying disease or by a change in medication, it should be treated directly. Modes of treatment include psychotherapy, tricyclic and related antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and electroconvulsive therapy.
IV. AMNESTIC SYNDROMES A disorder of memory (amnestic syndrome) may occur as one feature of an acute confusional state or dementia, or as an isolated abnormality (Table 1–30). The latter condition is discussed in this section.
Memory
Figure 1–19. T2-weighted MRI in multiinfarct dementia, showing foci of abnormal high signal intensity adjacent to the lateral ventricles (arrows) and within the basal ganglia (arrowheads).
Memory is a complex function that can be viewed for clinical purposes as comprising phases of registration, storage, and retrieval. Autopsy and imaging studies of the brains of patients with memory disorders suggest that the hippocampus and related structures, such as the dorsomedial nucleus of the thalamus, are important in memory processing. Bilateral damage to these regions results in impairment of short-term memory, which is manifested clinically by the inability to form new memories. Long-term memory, which involves retrieval of previously learned information, is relatively preserved, perhaps because well-established memories are stored
DISORDERS OF COGNITIVE FUNCTION / 63 Table 1–29. Dementia and the pseudodementia of depression: distinguishing features. Dementia
Depression
Insidious onset
Abrupt onset
Progressive deterioration
Plateau of dysfunction
No history of depression
History of depression may exist
Patient typically unaware of extent of deficits and does not complain of memory loss
Patient aware of and may exaggerate deficits and frequently complains of memory loss
Somatic complaints uncommon
Somatic complaints or hypochondriasis common
Variable affect
Depressed affect
Few vegetative symptoms
Prominent vegetative symptoms
Impairment often worse at night
Impairment usually not worse at night
Neurologic examination and laboratory studies may be abnormal
Neurologic examination and laboratory studies normal
diffusely in the cerebral cortex. Some patients with amnestic syndromes may attempt to fill in gaps in memory with false recollections (confabulation), which can take the form of elaborate contrivances or of genuine memories misplaced in time. The longest-standing and most deeply ingrained memories, however, such as one’s own name, are almost always spared in organic memory disturbances. In contrast, such personal memories may be prominently or exclusively impaired in dissociative (psychogenic) amnesia. The cellular basis of memory is poorly understood, but repetitive neuronal firing produces lasting pre- and postsynaptic changes that facilitate neurotransmission at hippocampal synapses (long-term potentiation). These changes appear to involve the release of glutamate, which stimulates the entry of calcium into post-
Table 1–30. Causes of amnestic syndromes. Acute Accompanying acute confusional states Head trauma Hypoxia or ischemia Bilateral posterior cerebral artery occlusion Transient global amnesia Alcoholic blackouts Wernicke encephalopathy Dissociative (psychogenic) amnesia Chronic Accompanying dementias Alcoholic Korsakoff amnestic syndrome Postencephalitic amnesia Brain tumor Paraneoplastic limbic encephalitis
synaptic neurons, and the production of retrograde signals that act on presynaptic nerve terminals to increase transmitter release upon subsequent firing.
ACUTE AMNESIA HEAD TRAUMA Head injuries resulting in loss of consciousness are invariably associated with an amnestic syndrome. Patients seen shortly after such an injury exhibit a confusional state in which they are unable to incorporate new memories (anterograde, or posttraumatic amnesia; see Figure 1–20), although they may behave in an apparently normal automatic fashion. In addition, retrograde amnesia is present, covering a variable period prior to the trauma. Features characteristic of transient global amnesia (see below) may be seen. As full consciousness returns, the ability to form new memories is restored. Events occurring in the confusional interval tend to be permanently lost to memory, however. Exceptions are islands of memory, for a lucid interval between trauma and unconsciousness, or for periods of lesser impairment in the course of a fluctuating posttraumatic confusional state. The period of retrograde amnesia begins to shrink, with the most remote memories the first to return. The severity of the injury tends to correlate with the duration of confusion and with the extent of permanent retrograde and posttraumatic amnesia.
HYPOXIA OR ISCHEMIA Because of the selective vulnerability of pyramidal neurons in the Sommer sector (h1 sector of Scholz) of the
64 / CHAPTER 1 Trauma
Recovery
Level of consciousness
Normal
Confused
Comatose
Retrograde amnesia
Anterograde amnesia
Time
Figure 1–20. Retrograde and anterograde amnesia in posttraumatic memory disorders. Head trauma may produce transient coma, followed by a confusional state during which the patient is unable to form new memories.With recovery, this ability is restored, but there is persistent amnesia for the period of coma and confusion (anterograde amnesia) and for a variable period preceding the trauma (retrograde amnesia); the latter deficit may improve with time.
hippocampus, conditions resulting in cerebral hypoxia or ischemia, such as cardiac arrest or carbon monoxide poisoning, can produce amnestic syndromes. Amnesia tends to occur in patients in whom coma has lasted at least 12 hours. There is severe impairment of the ability to incorporate new memories, with relative preservation of registration and remote memory; patients typically appear to have an isolated disorder of short-term memory. A period of retrograde amnesia preceding the insult may occur. Patients exhibit a lack of concern about their impairment and sometimes confabulate. Amnesia following cardiac arrest may be the sole manifestation of neurologic dysfunction, or it may coexist with other cerebral watershed syndromes, such as bibrachial paresis, cortical blindness, or visual agnosia (see Chapter 9). Recovery often occurs within several days, although deficits may persist. Amnestic syndromes from carbon monoxide poisoning are frequently associated with affective disturbances. Other associated abnormalities include focal cortical and extrapyramidal dysfunction. Acute carbon monoxide poisoning is suggested by cherry-red coloration of the skin and mucous membranes, elevated carboxyhemoglobin levels, or cardiac arrhythmia. The CT brain scan may show lucencies in the basal ganglia and dentate nuclei.
BILATERAL POSTERIOR CEREBRAL ARTERY OCCLUSION The posterior cerebral artery supplies the medial temporal lobe, thalamus, posterior internal capsule, and oc-
cipital cortex (Figure 1–21). Ischemia or infarction in this territory, typically when bilateral, may produce a transient or permanent amnestic syndrome. Emboli in the vertebrobasilar system (see Chapter 9) are frequent causes of such disorders. The amnestic syndrome is usually associated with unilateral or bilateral hemianopia and sometimes with visual agnosia, alexia without agraphia, anomia, sensory disturbances, or signs of upper midbrain dysfunction (especially impaired pupillary light reflex). Recent memory tends to be selectively impaired, with relative preservation of remote memory and registration. The CT scan shows lucencies—which may or may not be enhanced by use of contrast material—in any combination of the above-mentioned regions. Evaluation and treatment are described in Chapter 9.
TRANSIENT GLOBAL AMNESIA Transient global amnesia is a syndrome of acute memory loss that tends to occur in middle-aged or elderly patients with risk factors for atherosclerotic disease, especially a prior ischemic event in the posterior cerebral circulation. The disorder is recurrent in fewer than 10% of patients. A primary disorder of short-term memory that can last for minutes or days, it typically lasts for hours. Patients appear agitated and perplexed and may repeatedly inquire about their whereabouts, the time, and the nature of what they are experiencing. Knowledge of personal identity is preserved, as are remote memories and registration. New memories cannot be formed,
DISORDERS OF COGNITIVE FUNCTION / 65 (especially serotonin- or glutamate-mediated) neurotransmission. The disorder is self-limited and no specific treatment is required, but reduction of the ethanol intake should be counseled, and thiamine should be given to treat possible Wernicke encephalopathy (see p. 18).
WERNICKE ENCEPHALOPATHY Wernicke encephalopathy is caused by thiamine deficiency and classically produces an acute confusional state, ataxia, and ophthalmoplegia. Amnesia may be the major or sole cognitive disturbance, however, especially after thiamine treatment is begun and other cognitive abnormalities improve. Because patients with Wernicke encephalopathy usually present with global confusion rather than isolated amnesia, the disorder is discussed more fully above (see p. 18).
DISSOCIATIVE (PSYCHOGENIC) AMNESIA Figure 1–21. T1-weighted MRI in a patient with an old left posterior cerebral artery occlusion, showing tissue loss in the medial temporal (small arrows) and occipital (large arrows) lobes and associated dilation of the temporal and occipital horns of the lateral ventricle. (Courtesy of A Gean.) however, which accounts for the patient’s repetitive questions. Retrograde amnesia for a variable period preceding the episode may be present, but this period shrinks as the episode resolves. The patient’s obvious concern about the condition distinguishes transient global amnesia from most other organically based amnestic syndromes and may give rise to the suspicion that amnesia is psychogenic. A CT scan or MRI may demonstrate focal thalamic or temporal lobe abnormalities. Diffusion-weighted MRI has shown signal abnormalities in the temporal lobe during spells of transient global amnesia. These are compatible with cellular edema and may be related to spreading depression—a wave of cellular depolarization accompanied by cellular swelling in the brain.
ALCOHOLIC BLACKOUTS Short-term consumption of large amounts of ethanol by alcoholic or nonalcoholic individuals may lead to “blackouts”—transient amnestic episodes that are not due to global confusion, seizures, head trauma, or the Wernicke-Korsakoff syndrome. These spells are characterized by an inability to form new memories, without impairment of long-term memory or immediate recall. Although the cause is unknown, alcoholic blackouts may result from ethanol-induced depression of synaptic
Amnesia may be a manifestation of a dissociative disorder or of malingering. In such patients a prior psychiatric history, additional psychiatric symptoms, or a precipitating emotional stress can often be identified. Dissociative amnesia is characterized by an isolated or a disproportionate loss of traumatic or stressful personal memories. Dissociative amnesia is usually localized in time to the immediate aftermath of a traumatic experience or selective for some but not other events during such a period. Less frequent patterns include systematized amnesia restricted to certain categories of information, continuous amnesia for events from some time in the past up to and including the present, and generalized amnesia. In some cases, patients may be unable to remember even their own name—an exceedingly rare finding in organic amnesia. Despite such disorientation to person, orientation to place and time may be preserved. In addition, recent memories may be less affected than remote memories—the reverse of the pattern customarily seen in amnesia caused by organic disease. Examination under hypnosis or after administration of amobarbital sodium may be helpful in establishing that amnesia is of psychogenic origin.
CHRONIC AMNESIA ALCOHOLIC KORSAKOFF AMNESTIC SYNDROME The Korsakoff amnestic syndrome, which occurs in chronic alcoholism and other malnourished states, is thought to be caused by thiamine deficiency. It is usually preceded by one or more episodes of Wernicke encephalopathy, but such a history may be lacking. The memory disorder may be related to bilateral degeneration of the dorsomedial thalamic nuclei.
66 / CHAPTER 1 An amnestic syndrome of variable severity follows recovery from Wernicke encephalopathy in about three-fourths of cases and is often associated with polyneuropathy and other residua such as nystagmus or gait ataxia. The essential defect is an inability to form new memories, resulting in significant impairment of short-term memory. Long-term memory is also frequently affected, although to a lesser extent. Registration is intact. Patients are typically apathetic and lack insight into their disorder. They may attempt to reassure the physician that no impairment exists and try to explain away their obvious inability to remember. Confabulation is often, but not invariably, a feature. Korsakoff syndrome can be prevented or its severity decreased by prompt administration of thiamine to patients with Wernicke encephalopathy. Patients with established Korsakoff syndrome should also receive thiamine to prevent the progression of deficits, although existing deficits are unlikely to be reversed.
POSTENCEPHALITIC AMNESIA Patients who recover from acute viral encephalitis—particularly that caused by herpes simplex virus—may be left with a permanent and static amnestic syndrome. The syndrome is similar to that produced by chronic alcoholism in that an inability to form new memories is its outstanding feature. Remote memories are affected to a lesser extent than are recent ones, and registration is intact. Confabulation may occur. Often there is total amnesia for the period of the acute encephalitis. Patients may also exhibit other symptoms of limbic system disease. These include docility, indifference, flatness of mood and affect, inappropriate jocularity and sexual allusions, hyperphagia, impotence, repetitive stereotyped motor activity, and the absence of goal-oriented activity. Complex partial seizures, with or without secondary generalization, may occur.
BRAIN TUMOR Brain tumor is a rare cause of amnestic syndrome. Tumors that can present in this manner include those that are located in the third ventricle or that compress its floor or walls from without. The amnestic syndrome closely resembles Korsakoff syndrome. In addition, patients with deep midline tumors often exhibit marked lethargy, headache, endocrine disturbances, visual field deficits, or papilledema. The diagnosis of brain tumor is made by CT scan or MRI. Treatment consists of surgery or irradiation or both, depending upon the type of tumor and its location.
as a remote effect of systemic cancer. When limbic structures are primarily affected, the clinical picture is that of an amnestic syndrome. The disorder is thought to be autoimmune in origin since, as in other paraneoplastic neurologic syndromes, antineuronal autoantibodies can be detected. Paraneoplastic limbic encephalitis is most often associated with small-cell cancer of the lung, and symptoms typically precede diagnosis of the underlying cancer. Histopathologic findings include neuronal loss, reactive gliosis, microglial proliferation, and perivascular lymphocytic cuffing. Gray matter of the hippocampus, cingulum, piriform cortex, inferior frontal lobes, insula, and amygdala is characteristically affected. Symptoms develop over several weeks. The disorder is characterized by profound impairment of recent memory, corresponding to the inability to learn new material. Remote memory is less impaired, and registration is unaffected; confabulation occurs in some cases. Affective symptoms, either anxiety or depression, are common early features. Hallucinations and complex partial or generalized seizures may occur. In many instances, the amnestic syndrome progresses to a global dementia. Depending upon the extent to which gray matter regions outside the limbic system are involved, cerebellar, pyramidal, bulbar, and peripheral nerve disturbances may coexist with the amnestic disorder. The CSF may also show a modest mononuclear pleocytosis and mildly elevated protein. Diffuse slowing or bitemporal slow waves and spikes are sometimes seen on EEG. An MRI may reveal abnormal signal intensity in the medial temporal lobes. About 60% of patients have antineuronal antibodies in serum or CSF. Anti-Hu antibodies are most common and are usually associated with small-cell lung cancer and anti-Ta antibodies are seen in patients with testicular cancer; in both groups, prognosis is poor. Patients with neither anti-Hu nor anti-Ta antibodies have a better outcome and often improve after treatment of the underlying tumor. The paraneoplastic amnestic syndrome can be static, it can progress, or it can remit. Excluding other, especially treatable, disorders is of primary importance. Korsakoff syndrome caused by thiamine deficiency should be especially considered, because patients with cancer are susceptible to nutritional deficiency and thiamine administration may prevent these symptoms from worsening.
REFERENCES ACUTE CONFUSIONAL STATES
PARANEOPLASTIC LIMBIC ENCEPHALITIS
Metabolic Disorders
An inflammatory and degenerative disorder of gray matter regions of the central nervous system can occur
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Other Cerebral Disorders McKeith I et al: Dementia with Lewy bodies. Lancet Neurol 2004;3:19–28. Mendez MF et al: Frontotemporal dementia versus Alzheimer’s disease: differential cognitive features. Neurology 1996;47: 1189–1194. Riley DE et al: Cortical-basal ganglionic degeneration. Neurology 1990;40:1203–1212. Van Everbroeck B et al: Differential diagnosis of 201 possible Creutzfeldt-Jakob disease patients. J Neurol 2004;251:298– 304. Van Everbroeck B et al: A prospective study of CSF markers in 250 patients with possible Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiat 2003;74:1210–1214. Vanneste JA: Diagnosis and management of normal-pressure hydrocephalus. J Neurol 2000;247:5–14. Will RG et al: Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 2000;47:575–582.
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2
Headache & Facial Pain
CONTENTS Approach to diagnosis, 70 Pathophysiology of headache & facial pain, 70 History, 70 Physical examination, 73 Neurologic examination, 74 Headaches of acute onset, 74 Subarachnoid hemorrhage, 74 Other cerebrovascular disorders, 79 Meningitis or encephalitis, 80
Other causes of acute headache, 80 Headaches of subacute onset, 81 Giant cell arteritis, 81 Intracranial mass, 82 Idopathic Intracranial Hypertension, 83 Trigeminal neuralgia, 83 Glossopharyngeal neuralgia, 84 Postherpetic neuralgia, 84
Hypertension, 85 Atypical facial pain, 85 Chronic headaches, 85 Migraine, 85 Analgesic withdrawal headache, 90 Cluster headache, 90 Tension-type headache, 91 Ice pick pain, 92 Cervical spine disease, 92 Sinusitis, 92 Dental disease, 92
KEY CONCEPTS Headache results from disorders that affect painsensitive structures of the head and neck, such as meninges, blood vessels, nerves, and muscle.
urgent lumbar puncture and away from imaging procedures. Subarachnoid hemorrhage from a ruptured intracranial aneurysm often can be diagnosed by the presence of subarachnoid blood on a noncontrast CT scan; however, in the absence of this finding, a lumbar puncture showing no blood in the cerebrospinal fluid is required to exclude the diagnosis.
Headaches that are new in onset or different from previous headaches are those most likely to be caused by a serious illness, whereas headaches of long standing usually have a benign cause. Signs of meningeal irritation—such as neck stiffness on passive flexion in the anteroposterior direction or hip and knee flexion in response to passive neck flexion—must be sought in patients with acute headache; detecting these signs is critical in the rapid diagnosis of meningitis, and directs the diagnostic evaluation toward
High blood pressure alone does not cause chronic headache. For maximum effect, drugs for migraine should be taken immediately at the onset of symptoms.
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70 / CHAPTER 2 Headache occurs in all age groups and accounts for 1–2% of emergency department evaluations and for up to 4% of medical office visits; the causes are myriad (Table 2–1). Although most often a benign condition (especially when chronic and recurrent), headache of new onset may be the earliest or the principal manifestation of serious systemic or intracranial disease and therefore requires thorough and systematic evaluation. An etiologic diagnosis of headache is based on understanding the pathophysiology of head pain; obtaining a history, with characterization of the pain as acute, subacute, or chronic; performing a careful physical examination; and formulating a differential diagnosis.
APPROACH TO DIAGNOSIS PATHOPHYSIOLOGY OF HEADACHE & FACIAL PAIN Pain-Sensitive Structures Headache is caused by traction, displacement, inflammation, vascular spasm, or distention of the pain-sensitive structures in the head or neck. Isolated involvement of the bony skull, most of the dura, or most regions of brain parenchyma does not produce pain. A. PAIN-SENSITIVE STRUCTURES WITHIN THE CRANIAL VAULT These include the venous sinuses (eg, sagittal sinus); the anterior and middle meningeal arteries; the dura at the base of the skull; the trigeminal (V), glossopharyngeal (IX), and vagus (X) nerves; the proximal portions of the internal carotid artery and its branches near the Circle of Willis; the brainstem periaqueductal gray matter; and the sensory nuclei of the thalamus. B. EXTRACRANIAL PAIN-SENSITIVE STRUCTURES These include the periosteum of the skull; the skin; the subcutaneous tissues, muscles, and arteries; the neck muscles; the second and third cervical nerves; the eyes, ears, teeth, sinuses, and oropharynx; and the mucous membranes of the nasal cavity.
Radiation or Projection of Pain The trigeminal (V) nerve carries sensation from intracranial structures in the anterior and middle fossae of the skull, above the cerebellar tentorium. Discrete intracranial lesions in these locations can produce pain that radiates in the trigeminal nerve distribution (Figure 2–1). The glossopharyngeal (IX) and vagus (X) nerves supply part of the posterior fossa; pain originating in
Table 2–1. Causes of headache and facial pain. Acute onset Common causes Subarachnoid hemorrhage Other cerebrovascular diseases Meningitis or encephalitis Ocular disorders (glaucoma, acute iritis) Less common causes Seizures Lumbar puncture Hypertensive encephalopathy Coitus Subacute onset Giant cell (temporal) arteritis Intracranial mass (tumor, subdural hematoma, abscess) Pseudotumor cerebri (benign intracranial hypertension) Trigeminal neuralgia (tic douloureux) Glossopharyngeal neuralgia Posttherpetic neuralgia Hypertension (including pheochromocytoma and the use of monoamine oxidase inhibitors plus tyramine) Atypical facial pain Chronic Migraine Cluster headache Tension headache Cervical spine disease Sinusitis Dental disease
this area may also be referred to the ear or throat (eg, glossopharyngeal neuralgia). The upper cervical nerves transmit stimuli arising from infratentorial and cervical structures; therefore, pain from posterior fossa lesions projects to the second and third cervical dermatomes (Figure 2–1).
HISTORY Classification & Approach to the Differential Diagnosis A. ACUTE HEADACHES AND FACIAL PAIN Headaches that are new in onset and clearly different from any the patient has experienced previously are commonly a symptom of serious illness and therefore demand prompt evaluation. The sudden onset of “the worst headache I’ve ever had in my life” (classic subarachnoid hemorrhage), diffuse headache with neck stiffness and fever (meningitis), and head pain centered about one eye (acute glaucoma) are striking examples. Acute headaches may also accompany more benign processes such as viral syndromes or other febrile illnesses.
HEADACHE & FACIAL PAIN / 71 Anterior fossa
V1 V1, 2, 3 C2 C2, 3
Middle fossa
C1, 2, 3
V2 C3
Tentorium cerebelli C2, 3
Posterior fossa
V3 C4 C3, 4
A
B
Figure 2–1. Innervation of pain-sensitive intracranial compartments A and corresponding extracranial sites of pain radiation B.The trigeminal (V) nerve, especially its ophthalmic (V1) division, innervates the anterior and middle cranial fossae; lesions in these areas can produce frontal headache.The upper cervical nerve roots (especially C2) innervate the posterior fossa; lesions here can cause occipital headache.
B. SUBACUTE HEADACHES AND FACIAL PAIN Subacute headaches occur over a period of weeks to months. Such headaches may also signify serious medical disorders, especially when the pain is progressive or when it develops in elderly patients. Inquiries should be made about recent head trauma (subdural hematoma or postconcussive syndrome); a history of malaise, fever, or neck stiffness (subacute meningitis); other neurologic abnormalities or weight loss (primary or metastatic brain tumor); symptoms of vasculitis, especially giant cell arteritis; and medical conditions (eg, optic neuritis in multiple sclerosis; cutaneous herpes zoster) or medications predisposing to any of the disorders listed in Table 2–1. C. CHRONIC HEADACHES AND FACIAL PAIN Headaches that have occurred for years (eg, migraine or tension headaches) usually have a benign cause, although each acute attack may be profoundly disabling. When treating these patients, it is important to determine whether the present headache is similar to those suffered previously or is new—and thus represents a different process.
Precipitating Factors Precipitating factors can provide a guide to the cause of headache. Such factors include recent eye or dental surgery; acute exacerbation of chronic sinusitis or hay fever; systemic viral infection; tension, emotional stress, or fatigue; menses; hunger; ice cream; foods containing nitrite (hot dogs, salami, ham, and most sausage), phenylethylamine (chocolate), or tyramine (cheddar cheese); and bright lights. Precipitation of headache by alcohol is especially typical of cluster headache. Chewing and eating commonly trigger glossopharyngeal neuralgia, tic douloureux, and the jaw claudication of giant cell arteritis; these activities also trigger pain in patients with temporomandibular joint dysfunction. The use of oral contraceptive agents or other drugs such as nitrates may precipitate or exacerbate migraine and even lead to stroke. Intense headache can occur in response to coughing in patients with structural lesions in the posterior fossa; in other instances no specific cause for cough headache can be identified.
72 / CHAPTER 2
Prodromal Symptoms and Auras
Associated Symptoms
Prodromal symptoms or auras, such as scintillating scotomas or other visual changes, often occur with migraine; they may also occur in patients with a seizure disorder who present with postictal headaches.
Manifestations of underlying systemic disease can aid in the etiologic diagnosis of headache and should always be sought. Recent weight loss may accompany cancer, giant cell arteritis, or depression. Fever or chills may indicate systemic infection or meningitis. Dyspnea or other symptoms of heart disease raise the possibility of subacute infective endocarditis and resultant brain abscess. Visual disturbances suggest an ocular disorder (eg, glaucoma), migraine, or an intracranial process involving the optic nerve or tract or the central visual pathways. Nausea and vomiting are common in migraine and posttraumatic headache syndromes and can be seen in the course of mass lesions. Some patients with migraine also report that diarrhea accompanies the attacks. Photophobia may be prominent in migraine and acute meningitis or subarachnoid hemorrhage. Myalgias often accompany tension headaches, viral syndromes, and giant cell arteritis. Ipsilateral rhinorrhea and lacrimation during attacks typify cluster headache. Transient loss of consciousness may be a concomitant of both migraine and glossopharyngeal neuralgia.
Characteristics of Pain Headache or facial pain is most often described as throbbing; a dull, steady ache; or a jabbing, lancinating pain. Pulsating, throbbing pain is frequently ascribed to migraine, but it is equally common in patients with tension headache. A steady sensation of tightness or pressure is also commonly seen with tension headache. The pain produced by intracranial mass lesions is typically dull and steady. Sharp, lancinating pain suggests a neuritic cause such as trigeminal neuralgia. Ice picklike pain may be described by patients with migraine, cluster headache, or giant cell arteritis. Headache of virtually any description can occur in patients with migraine or brain tumors, however, so that the character of the pain alone does not provide a reliable etiologic guide.
Location of Pain Unilateral headache is an invariable feature of cluster headache and occurs in the majority of migraine attacks; most patients with tension headache report bilateral pain. Ocular or retroocular pain suggests a primary ophthalmologic disorder such as acute iritis or glaucoma, optic (II) nerve disease (eg, optic neuritis), or retroorbital inflammation (eg, Tolosa-Hunt syndrome). It is also common in migraine or cluster headache. Paranasal pain localized to one or several of the sinuses, often associated with tenderness in the overlying periosteum and skin, occurs with acute infection or outlet obstruction of these structures. Headache from intracranial mass lesions may be focal (“it hurts right here”), but even in such cases it is replaced by bioccipital and bifrontal pain when the intracranial pressure becomes elevated. Bandlike or occipital discomfort is commonly associated with tension headaches. Occipital localization can also occur with meningeal irritation from infection or hemorrhage and with disorders of the joints, muscles, or ligaments of the upper cervical spine. Pain within the first division of the trigeminal nerve (Figure 2–1B), characteristically described as burning in quality, is a common feature of postherpetic neuralgia. Lancinating pain localized to the second or third division of the trigeminal nerve (Figure 2–1B) suggests tic douloureux. The pharynx and external auditory meatus are the most frequent sites of pain caused by glossopharyngeal neuralgia.
Other Features of Headache A. TEMPORAL PATTERN OF HEADACHE Headaches from mass lesions are commonly maximal on awakening, as are sinus headaches. Headaches from mass lesions, however, increase in severity over time. Cluster headaches frequently awaken patients from sleep; they often recur at the same time each day or night. Tension headaches can develop whenever stressful situations occur and are often maximal at the end of a workday. Migraine headaches are episodic and may be worse during menses (Figure 2–2). B. CONDITIONS RELIEVING HEADACHE Migraine headaches are frequently relieved by darkness, sleep, vomiting, or pressing on the ipsilateral temporal artery, and their frequency is often diminished during pregnancy. Postlumbar-puncture and low-pressure headaches are typically relieved by recumbency, whereas headaches caused by intracranial mass lesions may be less severe with the patient standing. C. CONDITIONS EXACERBATING HEADACHE Discomfort exacerbated by rapid changes in head position or by events that transiently raise intracranial pressure, such as coughing and sneezing, is often associated with an intracranial mass but can occur in migraine. Anger, excitement, or irritation can precipitate or
HEADACHE & FACIAL PAIN / 73 B. PULSE Tachycardia can occur in a tense, anxious patient with a tension headache or accompany any severe pain. Paroxysmal headache associated with tachycardia and perspiration is characteristic of pheochromocytoma.
Migraine
Tension headache
Cluster headache
Brain tumor
0
3
6
9
12
Time (months)
Figure 2–2. Temporal patterns of headache. Migraine headache is episodic and may occur at varying intervals.Tension headache may be present every day. Cluster headache occurs in bouts separated by symptomfree periods. Headache caused by brain tumor often increases in severity with time.
worsen both migraine and tension headaches. Stooping, bending forward, sneezing, or blowing the nose characteristically worsens the pain of sinusitis. Postural headache (maximal when upright, nearly absent when lying down) occurs with low cerebrospinal fluid (CSF) pressure caused by lumbar puncture, head injury, or spontaneous spinal fluid leak. Fluctuations in intensity and duration of the headache with no obvious cause, especially when associated with similar fluctuations in mental status, are seen with subdural hematoma. D. HISTORY OF HEADACHE The characteristics of the present headache should be compared with those of previous occurrences, since headache with features different from those previously experienced calls for careful investigation.
PHYSICAL EXAMINATION A general physical examination is mandatory, since headache is a nonspecific accompaniment of many systemic disorders. If possible, the patient should be observed during an episode of headache or facial pain.
Vital Signs A. TEMPERATURE Although fever suggests a viral syndrome, meningitis, encephalitis, or brain abscess, headache from these causes can occur without fever. Moreover, headache can accompany any systemic infectious illness.
C. BLOOD PRESSURE Hypertension per se rarely causes headache unless the blood pressure elevation is acute, as with pheochromocytoma, or very high, as with early hypertensive encephalopathy. Chronic hypertension, however, is the major risk factor for stroke, which can be associated with acute headache. Subarachnoid hemorrhage is commonly followed by marked acute blood pressure elevation. D. RESPIRATION Hypercapnia from respiratory insufficiency from any cause can elevate intracranial pressure and produce headache.
General Physical Examination A. WEIGHT LOSS Weight loss or cachexia in a patient with headache suggests the presence of cancer or chronic infection. Polymyalgia rheumatica–giant cell arteritis syndromes can also be accompanied by weight loss. B. SKIN Focal cellulitis of the face or overlying the skull indicates local infection, which may be the source of intracranial abscess or venous sinus thrombosis. Cutaneous abnormalities elsewhere may suggest vasculitis (including that from meningococcemia), endocarditis, or cancer. The neurofibromas or café-au-lait spots of von Recklinghausen disease (neurofibromatosis) may be associated with benign or malignant intracranial tumors that can produce headache. Cutaneous angiomas sometimes accompany arteriovenous malformations (AVMs) of the central nervous system and may be associated with chronic headache—or acute headache if they bleed. Herpes zoster that affects the face and head most often involves the eye and the skin around the periorbital tissue, causing facial pain. C. SCALP, FACE, AND HEAD Scalp tenderness is characteristic of migraine headache, subdural hematoma, giant cell arteritis, and postherpetic neuralgia. Nodularity, erythema, or tenderness over the temporal artery suggests giant cell arteritis. Localized tenderness of the superficial temporal artery also accompanies acute migraine. Recent head trauma or a mass lesion can cause a localized area of tenderness. Paget disease, myeloma, or metastatic cancer of the skull may produce head pain that is boring in quality
74 / CHAPTER 2 and associated with skull tenderness. In Paget disease, arteriovenous shunting within bone may make the scalp feel warm. Disorders of the eyes, ears, or teeth may cause headache. Tooth percussion may reveal periodontal abscess. Sinus tenderness may indicate sinusitis. A bruit over the orbit or skull suggests an intracranial AVM, a carotid artery-cavernous sinus fistula, an aneurysm, or a meningioma. Lacerations of the tongue raise the possibility of postictal headache. Ipsilateral conjunctival injection, lacrimation, Horner syndrome, and rhinorrhea occur with cluster headache. Temporomandibular joint disease is accompanied by local tenderness and crepitus. D. NECK Cervical muscle spasms occur with tension and migraine headaches, cervical spine injuries, cervical arthritis, or meningitis. Carotid bruits may be associated with cerebrovascular disease. Meningeal signs must be carefully sought, especially if the headache is of recent onset. Meningeal irritation causes nuchal rigidity mainly in the anteroposterior direction, whereas cervical spine disorders restrict movement in all directions. Discomfort or hip and knee flexion during neck flexion (Brudzinski sign) readily indicates meningeal irritation (Figure 2–3). Meningeal signs may be absent or difficult to demonstrate in the early stages of subacute (eg, tuberculous) meningitis, in the first few hours after subarachnoid hemorrhage, and in comatose patients. E. HEART AND LUNG Brain abscess may be associated with congenital heart disease, which is evidenced by murmurs or cyanosis. Lung abscess may also be a source of brain abscess.
NEUROLOGIC EXAMINATION Mental Status Examination During the mental status examination, patients with acute headache may demonstrate confusion, as is commonly seen with subarachnoid hemorrhage and meningitis. Dementia may be the major feature of intracranial tumor, particularly one in the frontal lobe.
Cranial Nerve Examination Cranial nerve abnormalities may suggest and localize an intracranial tumor or other mass lesion. Papilledema, the hallmark of increased intracranial pressure, may be seen in space-occupying intracranial lesions, carotid artery-cavernous sinus fistula, pseudotumor cerebri, or hypertensive encephalopathy. Superficial retinal (subhyaloid) hemorrhages are characteristic of subarachnoid
hemorrhage in adults. Ischemic retinopathy may be found in patients with vasculitis. Progressive oculomotor nerve palsy, especially when it causes pupillary dilatation, may be the presenting sign of an expanding posterior-communicating-artery aneurysm, or it may reflect increasing intracranial pressure and incipient herniation. Decreased pupillary reactivity occurs in optic neuritis. Extraocular muscle palsies occur in Tolosa-Hunt syndrome. Proptosis suggests an orbital mass lesion or carotid artery-cavernous sinus fistula. Decreased sensation over the area of pain—most commonly the first division of the trigeminal nerve—is found in postherpetic neuralgia. Trigger areas eliciting pain in and about the face and pharynx suggest trigeminal and glossopharyngeal neuralgia, respectively.
Motor Examination Asymmetric motor function or gait ataxia in a patient with a history of subacute headache demands complete evaluation to exclude intracranial mass lesions.
Sensory Examination Focal or segmental sensory impairment or diminished corneal sensation (corneal reflex) is strong evidence against a benign cause of pain.
HEADACHES OF ACUTE ONSET Sudden onset of new headache may be a symptom of serious intracranial or systemic disease; it must be investigated promptly and thoroughly.
SUBARACHNOID HEMORRHAGE Spontaneous (nontraumatic) subarachnoid hemorrhage (bleeding into the subarachnoid space) is usually the result of a ruptured cerebral arterial aneurysm or an AVM. Rupture of a berry aneurysm accounts for about 75% of cases, with an annual incidence of 6 per 100,000. Rupture occurs most often during the fifth and sixth decades, with an approximately equal sex distribution. The risk of rupture of an intracranial aneurysm varies with patient age, and aneurysm site and size. Hypertension has not been conclusively demonstrated to predispose to the formation of aneurysms, but acute elevation of blood pressure (eg, at orgasm) may be responsible for their rupture. Intracranial AVMs, a less frequent cause of subarachnoid hemorrhage (10%), occur twice as often in men and usually bleed in the second to fourth decades, although a significant incidence extends into the 60s. Blood in the
HEADACHE & FACIAL PAIN / 75
Figure 2–3. Brudzinski sign. With the patient supine and the examiner’s hand on the patient’s chest, passive neck flexion (arrow at right) results in flexion at the hips (arrows at left), which is often asymmetric.The sign is present with meningeal irritation from disorders such as infectious meningitis or subarachnoid hemorrhage.
subarachnoid space can also result from intracerebral hemorrhage, embolic stroke, and trauma.
Pathology Cerebral artery aneurysms are most commonly congenital “berry” aneurysms, which result from developmental weakness of the vessel wall, especially at sites of
branching. These aneurysmal dilatations arise from intracranial arteries about the Circle of Willis at the base of the brain (Figure 2–4) and are multiple in about 20% of cases. Other congenital abnormalities, including polycystic kidney disease and coarctation of the aorta, may be associated with berry aneurysms. Occasionally, systemic infections such as infective endocarditis disseminate to a cerebral artery and cause aneurysm
76 / CHAPTER 2 Anterior communicating artery (15%)
Anterior cerebral artery (9%)
Posterior communicating artery (6%)
Middle cerebral artery (29%)
Internal carotid artery (16%)
Posterior cerebral artery (3%)
Basilar artery (14%)
Figure 2–5. Peripapillary intraretinal (streak-like) and Vertebral artery (6%)
preretinal or subhyaloid (globular) hemorrhages associated with a sudden increase in intracranial pressure caused by aneurysmal rupture. (Courtesy of WF Hoyt.)
Figure 2–4. Frequency and distribution of intracranial aneurysms.
formation; such “mycotic” aneurysms account for 2–3% of aneurysmal ruptures. Mycotic aneurysms are usually more distal (along the course of cerebral arteries) than are berry aneurysms. AVMs consist of abnormal vascular communications that permit arterial blood to enter the venous system without passing through a capillary bed. They are most common in the middle cerebral artery distribution.
Pathophysiology Rupture of an intracranial artery elevates intracranial pressure and distorts pain-sensitive structures, producing headache. Intracranial pressure may reach systemic perfusion pressure and acutely decrease cerebral blood flow; together with the concussive effect of the rupture, this is thought to cause the loss of consciousness that occurs at the onset in about 50% of patients. Rapid elevation of intracranial pressure can also produce subhyaloid retinal hemorrhages (Figure 2–5). Because aneurysmal hemorrhage is usually confined to the subarachnoid space, it does not produce a focal cerebral lesion. Prominent focal findings on neurologic examination are accordingly uncommon except with middle cerebral artery aneurysms. Ruptured AVMs, however, produce focal abnormalities that correspond to their parenchymal location.
Clinical Findings A. SYMPTOMS AND SIGNS The classic (but not invariable) presentation of subarachnoid hemorrhage is the sudden onset of an unusually severe generalized headache (“the worst headache I ever had in my life”). The absence of headache essentially precludes the diagnosis. Loss of consciousness at onset is frequent, as are vomiting and neck stiffness. Symptoms may begin at any time of day and during either rest or exertion. The most significant feature of the headache is that it is new. Milder but otherwise similar headaches may have occurred in the weeks prior to the acute event. These earlier headaches are probably the result of small prodromal hemorrhages (sentinel, or warning, hemorrhages) or aneurysmal stretch. The headache is not always severe, however, especially if the subarachnoid hemorrhage is from a ruptured AVM rather than an aneurysm. Although the duration of the hemorrhage is brief, the intensity of the headache may remain unchanged for several days and may subside only slowly over the next 2 weeks. A recrudescent headache usually signifies recurrent bleeding. Blood pressure frequently rises precipitously as a result of the hemorrhage. Meningeal irritation may induce temperature elevations to as high as 39°C (102.2°F) during the first 2 weeks. There is frequently
HEADACHE & FACIAL PAIN / 77 confusion, stupor, or coma. Nuchal rigidity and other evidence of meningeal irritation (see Figure 2–3) are common, but these signs may not occur for several hours after the onset of the headache. Preretinal globular subhyaloid hemorrhages (found in 20% of cases) are most suggestive of the diagnosis (see Figure 2–5). Because bleeding occurs mainly in the subarachnoid space in patients with aneurysmal rupture, prominent focal signs are uncommon on neurologic examination. When present, they may bear no relationship to the site of the aneurysm. An exception is oculomotor nerve palsy occurring ipsilateral to a posterior communicating artery aneurysm. Bilateral extensor plantar responses and VI nerve palsies are frequent. Ruptured AVMs may produce focal signs, such as hemiparesis, aphasia, or a defect of the visual fields. B. LABORATORY FINDINGS Patients presenting with subarachnoid hemorrhage are investigated first by computed tomography (CT) scan (Figure 2–6), which will usually confirm that hemorrhage has occurred and may help to identify a focal source. CT brain scanning will detect subarachnoid blood in more than 90% of patients with aneurysmal rupture. The test is most sensitive on the day bleeding occurs and in patients with al-
A
tered consciousness. Intracerebral or intraventricular blood, associated hydrocephalus, and infarction can also be identified. Aneurysms may not be evident on the CT scan, but most AVMs can be seen with contrast. Magnetic resonance imaging (MRI) is especially useful in detecting small AVMs localized to the brainstem (an area poorly seen on CT scan). If the CT scan fails to confirm the clinical diagnosis of subarachnoid hemorrhage, lumbar puncture is performed. The CSF examination usually reveals markedly elevated opening pressure; the fluid is grossly bloody and contains from 100,000 to more than 1 million red cells/mm3. As a result of the breakdown of hemoglobin from red cells, the supernatant of the centrifuged CSF becomes yellow-tinged (xanthochromic) within several hours (certainly by 12 hours) following the hemorrhage (see Chapter 11). White cells are initially present in the spinal fluid in the same proportion to red cells as in the peripheral blood. The chemical meningitis caused by blood in the subarachnoid space, however, may produce a pleocytosis of several thousand white blood cells during the first 48 hours and a reduction in CSF glucose between the fourth and eighth days after the hemorrhage. In the absence of pleocytosis, CSF glucose following subarachnoid hemorrhage is normal. The peripheral blood white count is often modestly elevated
B
Figure 2–6. A: Nonenhanced brain CT scan from a patient with an acute aneurysmal subarachnoid hemorrhage. Areas of high density (arrows) represent blood in the subarachnoid space at the base of the brain (most aneurysms occur in this region about the Circle of Willis; see Figure 2–4). B: A normal unenhanced brain CT scan of the same region. Interpeduncular cistern, arrow; suprasellar cistern, small arrow. (Courtesy of C Jungreis.)
78 / CHAPTER 2 but rarely exceeds 15,000 cells/mm3. The electrocardiogram (ECG) may reveal a host of abnormalities: peaked or deeply inverted T waves, short PR interval, or tall U waves. Once the diagnosis is confirmed, four-vessel cerebral arteriography is undertaken. Cerebral angiography of both the carotid and vertebral arteries should be performed to visualize the entire cerebral vascular anatomy, since multiple aneurysms occur in 20% of patients and AVMs are frequently supplied from multiple vessels. Angiography can be performed at the earliest time convenient for radiology department personnel; emergency studies in the middle of the night are rarely indicated. Angiography is a prerequisite to the rational planning of surgical treatment and is therefore not necessary for patients who are not surgical candidates, eg, those who are deeply comatose.
Differential Diagnosis The history of a sudden severe headache with confusion or obtundation, nuchal rigidity, a nonfocal neurologic examination, and bloody spinal fluid is highly specific for subarachnoid hemorrhage. Hypertensive intracerebral hemorrhage is also manifested by obtundation and hemorrhagic spinal fluid, but there are prominent focal findings. Bacterial meningitis is excluded by the CSF examination. Ruptured mycotic aneurysm is suggested by other signs of endocarditis. Traumatic spinal puncture can be excluded as the cause of bloody CSF by examination of the centrifuged CSF specimen. Because blood that results from traumatic lumbar puncture has not yet undergone enzymatic breakdown to bilirubin, centrifugation of the spinal fluid specimen reveals a colorless supernatant.
Complications & Sequelae A. RECURRENCE OF HEMORRHAGE Recurrence of aneurysmal hemorrhage (20% over 10–14 days) is the major acute complication and roughly doubles the mortality rate. Recurrence of hemorrhage from AVM is less common in the acute period. B. INTRAPARENCHYMAL EXTENSION OF HEMORRHAGE Although it is common for hemorrhages from an AVM to involve the cerebral parenchyma, this is far less common with aneurysm. Nevertheless, rupture of an aneurysm of the anterior cerebral or middle cerebral artery may direct a jet of blood into brain parenchyma, producing hemiparesis, aphasia, and sometimes transtentorial herniation. C. ARTERIAL VASOSPASM Delayed arterial narrowing, termed vasospasm, occurs
in vessels surrounded by subarachnoid blood and can lead to parenchymal ischemia in more than one-third of cases. Clinical ischemia typically does not appear before Day 4 after the hemorrhage, peaks at Day 10–14, and then spontaneously resolves. The diagnosis can be confirmed by transcranial Doppler or cerebral angiography. The severity of spasm is related to the amount of subarachnoid blood, and therefore is less common where less blood is usually seen, such as in traumatic subarachnoid hemorrhage or AVM. D. ACUTE OR SUBACUTE HYDROCEPHALUS Acute or subacute hydrocephalus may develop during the first day—or after several weeks—as a result of impaired CSF absorption in the subarachnoid space. Progressive somnolence, nonfocal findings, and impaired upgaze should suggest the diagnosis. E. SEIZURES Seizures occur in fewer than 10% of cases and only following damage to the cerebral cortex. Decorticate or decerebrate posturing is common acutely, and may be mistaken for seizures. F. OTHER COMPLICATIONS Although inappropriate secretion of antidiuretic hormone and resultant diabetes insipidus can occur, they are uncommon.
Treatment A. MEDICAL TREATMENT Medical treatment is directed toward preventing elevation of arterial or intracranial pressure that might rerupture the aneurysm or AVM. Typical measures include absolute bed rest with the head of the bed elevated 15–20 degrees, mild sedation, and analgesics for headache. Drugs impairing platelet function (eg, aspirin) should be avoided. Because patients who are hypertensive on admission have an increased mortality risk, reducing the blood pressure (to approximately 160/100 mm Hg) is prudent. Bed rest and mild sedation are often adequate in this regard. Hypotension should be prevented, however, to ensure adequate cerebral perfusion. Intravenous fluids should be administered with care, since overhydration can exacerbate cerebral swelling. Intravenous fluids should be isoosmotic to minimize free water exacerbating brain edema. Normal saline can be given in amounts to ensure normovolemia. Hyponatremia is frequently seen, and usually represents, at least in part, cerebral salt wasting; it should be managed with sodium replacement such as NaCl orally or 3% normal saline intravenously rather than fluid restriction. Prophylactic use of the calcium channel antagonist drug nimodipine, 60 mg orally (or by nasogastric tube) every 4 hours for 21 days, may re-
HEADACHE & FACIAL PAIN / 79 duce the ischemic sequelae of cerebral vasospasm in patients with a ruptured aneurysm. Vasospasm is treated by induced hypertension with phenylephrine or dopamine; this intervention is more safely performed after definitive surgical treatment of the aneurysm. Although seizures are uncommon after aneurysmal rupture, the hypertension accompanying a seizure increases the risk of rerupture; a prophylactic anticonvulsant (eg, phenytoin, 300 mg/d) is therefore recommended routinely. B. SURGICAL TREATMENT 1. Aneurysm—Definitive surgical therapy of a ruptured aneurysm consists of clipping the neck of the aneurysm or the endovascular placement of a coil to induce clotting. The neurologic examination is used to grade the patient’s clinical state relative to surgical candidacy (Table 2–2). In patients who are fully alert (grades I and II) or only mildly confused (grade III), surgery has been shown to improve the clinical outcome. In contrast, stuporous (grade IV) or comatose (grade V) patients do not appear to benefit from the procedures. Although there is some controversy about the optimal timing of surgery, current evidence supports early intervention, within about 2 days following the hemorrhage. This approach reduces the period at risk for rebleeding and permits aggressive treatment of vasospasm with volume expansion and pharmacologic elevation of blood pressure. Treatment of unruptured aneurysm is individualized. Surgery is favored by young age, previous rupture, family history of aneurysmal rupture, observed aneurysm growth, and low operative risk. Decreased life expectancy and asymptomatic small aneurysms (<7 cms) favor conservative management. 2. AVMs—Surgically accessible AVMs may be removed by en bloc resection or obliterated by ligation of feeding vessels or embolization via local intraarterial catheter. Because the risk of an early second hemorrhage is much less with AVMs than with aneurysms, surgical treatment can be undertaken electively at a
convenient time after the bleeding episode.
Prognosis The mortality rate from aneurysmal subarachnoid hemorrhage is high. About 20% of patients die before reaching a hospital, 25% die subsequently from the initial hemorrhage or its complications, and 20% die from rebleeding if the aneurysm is not surgically corrected. Most deaths occur in the first few days after the hemorrhage. The probability of survival following aneurysmal rupture is related to the patient’s state of consciousness and the elapsed time since the hemorrhage. On Day 1, the prognosis for survival for symptom-free and somnolent patients is, respectively, 60% and 30%; such patients still alive at 1 month have survival probabilities of 90% and 60%, respectively. Of survivors, half have permanent brain injury. Recovery from subarachnoid hemorrhage resulting from rupture of intracerebral AVMs occurs in nearly 90% of patients, and although recurrent hemorrhage remains a danger, conservative management compares favorably with surgical therapy.
Familial Intracranial Aneurysms Families with two or more affected persons should have all members screened. Both autosomal and recessive patterns of inheritance occur.
OTHER CEREBROVASCULAR DISORDERS Headache may be associated with—or rarely may be the presenting symptom of—thrombotic or embolic stroke. Compression of pain-sensitive structures is the mechanism of headache in intracranial hemorrhage, whereas pain-sensitive receptors in large cerebral arteries are responsible for headache in thrombotic and embolic stroke. Lacunar strokes, which affect small arterial branches deep in the brain, are not as frequently associated with headache. Headaches associated with ischemic stroke are typi-
Table 2–2. Clinical grading of patients with aneurysmal subarachnoid hemorrhage. Grade
Level of Consciousness
Associated Clinical Features
Surgical Candidate
I
Normal
None or mild headache and stiff neck
Yes
II
Normal
Moderate headache and stiff neck; minimal neurologic deficit (eg, cranial nerve palsy) in some cases
Yes
III
Confusional state
Focal neurologic deficits in some cases
Yes
IV
Stupor
Focal neurologic deficits in some cases
No
V
Coma
Decerebrate posturing in some cases
No
80 / CHAPTER 2 cally mild to moderate in intensity, ipsilateral to the involved hemisphere, and nonthrobbing in character. Their location is determined by the pain projection sites of the involved arteries: posterior fossa strokes usually present with occipital headache, whereas carotid lesions usually produce frontal (trigeminal distribution) pain. Transient ischemic attacks may be associated with headache in as many as 50% of cases; in perhaps one-third of these, headaches precede the other symptoms. Headache accompanying retinal artery embolism or posterior cerebral artery spasm or occlusion may be erroneously diagnosed as migraine because of the associated visual impairment. Headache also occurs following carotid endarterectomy and may be associated with focal sensory or motor signs of contralateral hemispheric ischemia. This syndrome occurs in the presence of a patent carotid artery on the second or third postoperative day and typically produces intense throbbing anterior headache that is often associated with nausea. Headache disorders associated with ischemic or hemorrhagic cerebral infarction require direct treatment of the cerebral lesion combined with the use of analgesics for symptomatic relief.
MENINGITIS OR ENCEPHALITIS Headache is a prominent feature of inflammation of the brain (encephalitis) or its meningeal coverings (meningitis) caused by bacterial, viral, or other infections; granulomatous processes; neoplasms; or chemical irritants. The pain is caused by inflammation of intracranial pain-sensitive structures, including blood vessels at the base of the brain. The headache syndrome produced is commonly throbbing in character, bilateral, and occipital or nuchal in location. The headache is increased by sitting upright, moving the head, compressing the jugular vein, or performing other maneuvers (eg, sneezing, coughing) that transiently increase intracranial pressure. Photophobia may be prominent. The headache rarely presents suddenly but more commonly develops over hours to days, especially with subacute infections (eg, tuberculous meningitis). Neck stiffness and other signs of meningeal irritation (see Figure 2–3) must be sought with care, since they may not be obvious either early in the course of the illness or when the brain parenchyma, rather than meninges, is the predominant site of involvement. Lethargy or confusion also may be a prominent feature. The diagnosis is suggested by a CSF examination that shows an increased white blood cell count. Bacterial, syphilitic, tuberculous, viral, fungal, and parasitic infections may be distinguished by CSF VDRL, Gram stain, acid-fast stain, India ink preparation and cryptococcal antibody assays, and cultures (see Table 1–9).
Treatment of meningitis or encephalitis caused by these different organisms is discussed in Chapter 1.
OTHER CAUSES OF ACUTE HEADACHE 1. SEIZURES Postictal headache that follows generalized tonic-clonic seizures is frequently accompanied by resolving lethargy, diffuse muscle soreness, or tongue laceration. Although this headache requires no specific treatment, it is important to differentiate it from subarachnoid hemorrhage and meningitis. If doubt exists, lumbar puncture should be undertaken. 2. LUMBAR PUNCTURE Postlumbar-puncture headache is diagnosed by a history of lumbar puncture—and by the characteristic marked increase in pain in the upright position and relief with recumbency. The pain is typically occipital, comes on 24–48 hours after the procedure (although it may be later), and lasts 1–2 days, but may be prolonged. Headache is caused by persistent spinal subarachnoid leak with resultant traction on pain-sensitive structures at the base of the brain. The risk of this complication can be reduced by using a small-gauge needle (22 gauge or smaller) for the puncture and removing only as much fluid as needed for the studies to be performed. Lying flat afterward, for any length of time, does not lessen the incidence. Low-pressure headache syndromes are usually self-limited. When this is not the case, they may respond to the administration of caffeine sodium benzoate, 500 mg intravenously, which can be repeated after 45 minutes if headache persists or recurs upon standing. In persistent cases, the subarachnoid rent can be sealed by injection of autologous blood into the epidural space at the site of the puncture; this requires an experienced anesthesiologist. Headache similar in character to that caused by lumbar puncture occasionally occurs spontaneously. T1weighted, gadolinium-enhanced MRI may show smooth enhancement of the pachymeninges and a “sagging brain”) (Figure 2–7); the enhancement may be confused with disorders producing leptomeningeal inflammation. Low CSF pressure can also produce this MRI picture in the absence of headache. 3. HYPERTENSIVE ENCEPHALOPATHY Headache may be due to a sudden elevation in blood pressure caused by pheochromocytoma, sexual intercourse, the combination of monoamine oxidase inhibitors and tyramine-containing foods such as cheddar cheese, or—the most important cause—malignant hypertension. Blood pressures of 250/150 mm Hg or higher—characteristic of malignant hypertension— produce cerebral edema and displace pain-sensitive structures. The pain is described as severe and throb-
HEADACHE & FACIAL PAIN / 81
Figure 2–7. Spontaneous intracranial hypotension in a 27-year-old woman presenting with severe postural headaches. Sagittal and axial T1-weighted images obtained after gadolinium injections show features of “sagging brain”: downward displacement of the cerebellar tonsils into the foramen magnum (arrows, left image), effacement of the brainstem cisterns (left image; compare with normal sagittal MRI in Figure 11–3), and diffuse dural enhancement (arrows, right image). MRI abnormalities and symptoms reversed following an epidural blood patch. (Courtesy of HA Rowley.) bing. Other signs of diffuse or focal central nervous system dysfunction are present, such as lethargy, hemiparesis, or focal seizures; on CT or MRI images, posterior white matter changes may be seen (see Figure 1–10). Treatment is with antihypertensive drugs (see Chapter 1), but care must be taken to avoid hypotension, which can result in cerebral ischemia and stroke. 4. COITUS Headache during sexual intercourse has been described as the presenting sign of subarachnoid hemorrhage; however, headache in this setting is more often of a benign nature. Men are more often affected than women. The pain may be either a dull, bilateral pain occurring during sexual excitement or a severe, sudden headache occurring at the time of orgasm, presumably caused by a marked increase in systemic blood pressure. Persistent headache following orgasm—worse in the upright posture—has also been described. In the latter case, the symptoms are reminiscent of postlumbar-puncture headache and patients have low opening pressures at lumbar puncture. Each of these headaches—except for those associated with aneurysmal rupture—is benign and subsides over minutes to days. Patients reporting severe headache in association with orgasm should be evaluated for possible subarachnoid hemorrhage as described on p 75. If no hemor-
rhage is found, prophylactic treatment with indomethacin, 50 mg orally prior to intercourse, may be effective. 5. OCULAR DISORDERS Pain about the eye may occur in migraine and cluster headache and is also the presenting feature of iritis and glaucoma. Acute iritis produces extreme eye pain that is associated with photophobia. The diagnosis is confirmed by slit lamp examination; acute management involves pharmacologic dilatation of the pupil. Angleclosure glaucoma produces pain within the globe that radiates to the forehead. When it occurs after middle age, such a pain syndrome should prompt diagnostic tonometry. Acute treatment is with glycerol, 1 mL/kg orally, followed by pilocarpine, 2%, two drops every 15 minutes.
HEADACHES OF SUBACUTE ONSET GIANT CELL ARTERITIS This disorder, also known as temporal arteritis, is char-
82 / CHAPTER 2 acterized by a subacute granulomatous inflammation (consisting of lymphocytes, neutrophils, and giant cells) that affects the external carotid arterial system, particularly the superficial temporal artery, and the vertebral artery. Inflammation of the pain-sensitive arterial wall produces the headache. Thrombosis may occur in the most severely affected arteries. This syndrome, which affects women twice as frequently as men, is uncommon before age 50 and is frequently associated with malaise, myalgia, weight loss, arthralgia, and fever (the polymyalgia rheumatica complex). The headache can be unilateral or bilateral, fairly severe, and boring in quality. It is characteristically localized to the scalp, especially over the temporal arteries. Scalp tenderness may be especially apparent when lying with the head on a pillow or brushing the hair. Pain or stiffness in the jaw during chewing (jaw claudication) is highly suggestive of giant cell arteritis and is due to arterial ischemia in the muscles of mastication. Involvement of the ophthalmic artery leads to permanent blindness in 50% of untreated patients; in half of these, blindness will become bilateral. The visual loss is most often sudden in onset. Although episodes of transient prodromal blindness have been reported, blindness is unusual as an initial symptom; however, it often occurs within the first month. The diagnosis is made by biopsy of affected temporal arteries, which are characteristically thickened and nonpulsatile as well as dilated and tender. The temporal arteries may be affected in a patchy manner, and serial sections may be necessary to demonstrate histologic vasculitis. The erythrocyte sedimentation rate (ESR) is almost invariably elevated. The mean Westergren ESR is about 100 mm/h in giant cell arteritis (range, 29–144 mm/h) and in polymyalgia rheumatica (range, 58–160 mm/h). The normal upper limit of the Westergren ESR in elderly patients is reported to be only as high as 40 mm/h. Consideration of this diagnosis demands prompt evaluation to avoid visual loss. Initial therapy is with prednisone, 40–60 mg/d orally. The dose is decreased,
usually after 1–2 months, depending upon the clinical response. Some centers begin with intravenous methylprednisolone (500–1000 mg every 12 hours for two days). The sedimentation rate returns rapidly toward normal with prednisone therapy and must be maintained within normal limits as the drug dose is tapered. Therapy should not be withheld pending biopsy diagnosis and should be continued despite negative biopsy findings if the diagnosis can be made with confidence on clinical grounds. Tapering of prednisone therapy requires 1–2 years. Although dramatic improvement in headache occurs within 2–3 days after institution of therapy, the blindness is usually irreversible.
INTRACRANIAL MASS The new onset of headache in middle or later life should always raise concern about a mass lesion. A mass lesion, such as a brain tumor (Table 2–3), subdural hematoma, or abscess, may or may not produce headache depending upon whether it compresses or distorts pain-sensitive intracranial structures. Only 30% of patients with intracranial tumor present with headache as the first symptom, although 80% have such a complaint at the time of diagnosis. Subdural hematoma frequently presents with conspicuous headache, since its large size increases the likelihood of impinging upon pain-sensitive areas. Headaches associated with brain tumors are most often nonspecific in character, mild to moderate in severity, dull and steady in nature, and intermittent. The pain is characteristically bifrontal, worse ipsilaterally, and aggravated by a change in position or by maneuvers that increase intracranial pressure, such as coughing, sneezing, and straining at stool. The headache is classically maximal on awakening in the morning and is associated with nausea and vomiting. An uncommon type of headache that suggests brain tumor is characterized by a sudden onset of severe pain reaching maximal intensity within seconds, persisting for minutes to hours, and subsiding rapidly. Altered
Table 2–3. Symptoms of brain tumors. Percent with Symptom Symptom
Low-Grade Glioma
Malignant Glioma
Meningioma (Benign)
40
50
36
Seizure
65–95
15–25
40
Hemiparesis
5–15
30–50
22
10
40–60
21
Headache
Altered mental status
Modified from DeAngelis LM: Brain tumors. N Engl J Med 2001;344:114.
HEADACHE & FACIAL PAIN / 83 consciousness or “drop attacks” may be associated. Although classically associated with third ventricular colloid cysts, these paroxysmal headaches can be associated with tumors at many different intracranial sites. Suspicion of an intracranial mass lesion demands prompt evaluation, preferably with CT scan or MRI; brain tumor is excluded by a normal contrast-enhanced brain MRI scan.
Idiopathic Intracranial Hypertension Idiopathic intracranial hypertension (pseudotumor cerebri) is characterized by a diffuse increase in intracranial pressure causing headache, papilledema, pulsatile tinnitus, visual loss and diplopia as a result of abducens nerve palsy. Although intracranial hypertension can accompany many disorders (Table 2–4), most cases are idiopathic. In the idiopathic variety, women are affected much more commonly than men, with a peak incidence in the third decade. Most patients are obese. Diffuse headache is almost always a presenting symptom. Transient visual obscurations (lasting for seconds) and visual blurring occur in most cases. Visual acuity is normal in most patients at presentation; moderate to severe papilledema is seen in almost all. Visual loss from increased intracranial pressure, like that of glaucoma, is characterized by gradually constricting visual fields with late loss of central acuity. The symptomatic intracranial hypertension is generally self-limited over several months. Even though the papilledema may disappear, CSF pressure remains elevated for years and recurrent symptomatic episodes occur in 10%. Differentiating idiopathic pseudotumor cerebri from intracerebral mass lesions and from the disorders listed in Table 2–4 is critical; evaluation must include MRI or CT brain scanning and lumbar puncture. Imaging studies may show small (slitlike) ventricles and demonstrate an empty sella in 70% of instances. Dilation of the optic nerve sheath and flattening of the back of the globe are characteristic. Elevation of intracranial pressure can be documented by
lumbar puncture; removal of 20–40 ml CSF may transiently relieve headache. Cells, glucose, and protein content of the CSF are normal. If a specific cause is identified (Table 2–4), it must be treated appropriately. Treatment with acetazolamide 1–2 g/d or, furosemide 40–60 mg twice daily, is the mainstay of treatment. Corticosteroids are effective but have untoward side effects and papilledema tends to rebound when they are discontinued. In refractory cases, optic nerve sheath fenestration, or lumboperitoneal or ventriculoperitoneal shunting may be needed to protect vision and decrease headache.
TRIGEMINAL NEURALGIA Trigeminal neuralgia (tic douloureux) is a facial-pain syndrome of unknown cause that develops in middle to late life. In many instances, the trigeminal nerve roots are close to a vascular structure, and microvascular compression of the nerve is believed to cause the disorder. Pain is confined mainly to the area supplied by the second and third divisions of the trigeminal nerve (Figure 2–8). Involvement of the first division or bilateral disease occurs in less than 5% of cases. Characteristically, lightninglike momentary jabs of excruciating pain occur and spontaneously abate. Occurrence during sleep is rare. Pain-free intervals may last for minutes to weeks, but long-term spontaneous remission is rare. Sensory stimulation of
Pain
Table 2–4. Disorders associated with intracranial hypertension. Intracranial venous drainage obstruction (eg, venous sinus thrombosis, head trauma, polycythemia, thrombocytosis) Endocrine dysfunction (eg, obesity, withdrawal from steroid therapy; Addison disease; hypoparathyroidism) Vitamin and drug therapy (eg, hypervitaminosis A and 13 cis retinoic acid in children and adolescents; severe iron deficiency anemia; tetracycline, minocycline, nalidixic acid) Other (eg, chronic hypercapnia, severe right heart failure, chronic meningitis, hypertensive encephalopathy) Idiopathic
Figure 2–8. Distribution of symptoms in trigeminal neuralgia.
84 / CHAPTER 2 trigger zones about the cheek, nose, or mouth by touch, cold, wind, talking, or chewing can precipitate the pain. Physical examination discloses no abnormalities. Rarely, similar pain may occur in multiple sclerosis or brainstem tumors, and these possibilities should thus be considered in young patients and in all patients who show neurologic abnormalities on examination. In idiopathic cases, CT scan and MRI fail to show any abnormality, and arteriography is similarly normal. Any vascular structure compressing the nerve roots is generally too small to be seen by these means. Remission of symptoms with carbamazepine, 400–1200 mg/d orally in three divided doses, occurs within 24 hours in a high percentage of cases. Rarely, blood dyscrasia occurs as an adverse reaction to carbamazepine. The recent availability of oxcarbazepine (600–1800 mg/d in two divided doses) appears equally effective; blood dyscrasias have not been reported. Intravenous administration of phenytoin, 250 mg, will abort an acute attack, and phenytoin, 200–400 mg/d orally, may be effective alone or in combination with carbamazepine if a second drug is necessary. Lamotrigine 400 mg/d or baclofen 10 mg three times daily– 20 mg four times daily has been used in refractory cases. Posterior fossa microvascular decompressive surgery has been used in drug-resistant cases.
GLOSSOPHARYNGEAL NEURALGIA Patients with glossopharyngeal neuralgia, an uncommon pain syndrome, present with either a paroxysmal pain that is identical in quality to that of trigeminal neuralgia, or a continuous burning or aching discomfort. The pain is localized to the oropharynx, the tonsillar pillars, the base of the tongue, or the auditory meatus. The trigger areas are usually around the tonsillar pillars, so that symptoms are initiated by swallowing or by talking. Paroxysms of pain can occur many times daily and may be accompanied by syncopal episodes caused by transient bradyarrhythmias. Men are affected more often than women, and symptoms begin at a somewhat younger age than in trigeminal neuralgia. The diagnosis is established by the history and by reproducing pain through stimulation of the trigger zones (usually about the tonsillar regions). Examination reveals no abnormal neurologic signs. Application of local anesthetics to the trigger area may block the pain response. Carbamazepine or phenytoin therapy (as described above for trigeminal neuralgia) usually produces dramatic relief; microvascular decompression has been used.
virus in patients with a history of varicella infection. It does not occur before age 50 and becomes increasingly common with advancing age (70% in those over 70 years), in immunocompromised patients, and in patients with certain malignant diseases (eg, leukemia, lymphoma). Postherpetic neuralgia is characterized by constant, severe, stabbing or burning, dysesthetic pain that may persist for months or years in a minority of patients, especially the elderly. Pain occurs in the same dermatomal distribution as a previous bout of herpes zoster, conforming to the distribution of the involved nerve root, where residual scars may be present. When the head is involved, the first division of the trigeminal nerve is most commonly affected, so that pain is usually localized to the forehead on one side (Figure 2–9). Careful testing of the painful area reveals decreased cutaneous sensitivity to pinprick. The other major complication of trigeminal herpes is decreased corneal sensation with impaired blink reflex, which can lead to corneal abrasion, scarring, and ultimate loss of vision. The intensity and duration of the cutaneous eruption and the acute pain of herpes zoster are reduced by 7 to 10 days of treatment with acyclovir (800 mg 5 times daily), famcicloviror, or valacyclovir, but this treatment has not been shown to lessen the likelihood of postherpetic neuralgia. Corticosteroids (60 mg/d prednisone, orally for 2 weeks, with rapid tapering) taken during the acute herpetic eruption also reduce the incidence of
Scars
Pain and hypesthesia
POSTHERPETIC NEURALGIA Herpes zoster—a vesicular skin eruption in dermatomal distribution, accompanied and followed by local pain and tenderness—is due to reactivation of varicella-zoster
Figure 2–9. Distribution of symptoms and signs in postherpetic neuralgia.
HEADACHE & FACIAL PAIN / 85 acute herpetic pain, but have an uncertain effect on postherpetic pain. Once the postherpetic pain syndrome is established, the most useful treatment has been with tricyclic antidepressants such as amitriptyline, 25–150 mg/d orally, which are thought to act directly on central nervous system pain-integration pathways (rather than via an antidepressant effect); amitriptyline may be better tolerated. Tricyclic antidepressant drugs may be more effective when combined with a phenothiazine, as in the commercially available preparation Triavil. Gabapentin (1800–3600 mg/d) has shown some effect. Carbamazepine and phenytoin in anticonvulsant doses also have been used. Postherpetic neuralgia subsides within 6–12 months in many patients but in 50% of those over 70 years the pain persists. Lidocaine-prilocaine 2.5% cream, or lidocaine 5% gel or cutaneous patch, is effective topical therapy. Topical application of capsaicin cream (eg, Zostrix 0.025%), which depletes pain-mediating peptides from peripheral sensory neurons, also can be helpful but is poorly tolerated. In otherwise intractable cases, weekly intrathecal administration of methylprednisolone may reduce pain.
HYPERTENSION Chronic hypertension is often invoked as a cause of headache, but evidence to support such a connection is sparse. In contrast, headache is a well-established complication of paroxysmal hypertension such as seen in patients with pheochromocytoma or those ingesting tyramine-rich foods while being treated with monoamine oxidase inhibitors. In pheochromocytoma, headache attacks are brief. They last less than 15 minutes in one-half of patients and are characteristically associated with perspiration and tachycardia. The headache is usually bilateral and may be precipitated by urination if the bladder is involved.
ATYPICAL FACIAL PAIN Constant, boring, mainly unilateral lower facial pain for which no cause can be found is referred to as atypical facial pain. Unlike trigeminal neuralgia, it is not confined to the trigeminal nerve distribution and is not paroxysmal. This idiopathic disorder must be distinguished from similar pain syndromes related to nasopharyngeal carcinoma, intracranial extension of squamous cell carcinoma of the face, or infection at the site of a tooth extraction. Treatment is with amitriptyline, 20–250 mg/d orally, alone or in combination with phenelzine, 30–75 mg/d orally. Dilantin can be an effective alternative, especially if a tricyclic is inappropriate.
CHRONIC HEADACHES
MIGRAINE Migraine is manifested by headache that is usually unilateral and frequently pulsatile in quality; it is often associated with nausea, vomiting, photophobia, phonophobia, and lassitude. Visual or other neurologic auras occur in about 10% of patients. Two-thirds to threefourths of cases of migraine occur in women; the onset is early in life—approximately 25% beginning during the first decade, 55% by 20 years of age, and more than 90% before age 40. A family history of migraine is present in most cases.
Genetics of Migraine The aggregation of migraine within families has long been recognized, although consistent mendelian patterns of inheritance have not been found among the collective group of familial migraineurs. Presumably this reflects a variety of inheritance patterns, variable penetrance, and possibly multiple genes interacting with environmental factors in the multigenic/multifactorial pattern characteristic of complex diseases. Concordance rates in monozygotic twins of only 28–52% attest to the genetic component, but also predict a significant environmental contribution. A rare subtype of migraine with aura, familial hemiplegic migraine, has a straightforward autosomal dominant, highly penetrant inheritance pattern indicative of a strong genetic component. Three genetic loci for familial hemiplegic migraine have been identified: one on chromosome 19p13 (associated with missense mutations in a brain-expressed, voltage-gated P/Q calcium channel gene) and two neighboring loci on chromosome 1q.
Pathogenesis Intracranial vasoconstriction and extracranial vasodilatation have long been held to be the respective causes of the aura and headache phases of migraine. This theory received support from the efficacy of vasoconstrictive ergot alkaloids (eg, ergotamine) in aborting the acute migraine attack and vasodilators such as amyl nitrite in abolishing the migraine aura. More recent studies of regional cerebral blood flow during migraine attacks have demonstrated a reduction in regional flow, which begins in the occipital region, during the aura phase. The “spreading depression” in cerebral blood flow, however, proceeds according to cytoarchitectural patterns in the cerebral cortex and does not reflect the distribution of major vascular territories (Figure 2–10). In addition, the areas of decreased blood flow do not correspond to the cortical areas responsible for the particular aura, and regional cerebral blood flow may remain depressed after focal neurologic symptoms have resolved and headache has begun (Figure 2–11). Later
86 / CHAPTER 2 Central sulcus
Occipital pole
Figure 2–10. Direction of spread (arrows) and maximal extent (colored region) of depressed cerebral blood flow (CBF) in migraine with and without aura.These processes may be initiated by contralateral brainstem structures as increases in brainstem CBF during migraine persist after headache treatment with sumatriptan.
in the headache phase, blood flow increases to parts of the cortex (cingulate, auditory, and visual association areas) and the contralateral brainstem (serotonergic dorsal raphe nucleus and adrenergic nucleus ceruleus); treatment with effective agents (sumatriptan, ergotamine) attenuates the cortical but not brainstem changes. These data imply that cerebral blood flow changes and headache generation in migraine may be secondary to a primary disturbance in neuronal func-
Cerebral blood flow
Aura
Headache
Increased
Normal
Decreased
Time
Figure 2–11. Time course of changes in cerebral blood flow in migraine with aura. (Adapted from Olesen J et al: Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol 1990;28:791–798.)
tion in the brainstem. Brainstem stimulation in the periaqueductal gray and dorsal raphe nucleus produces migraine-like headache in humans. Serotonergic neurons ramify extensively throughout the brain, and many effective antimigraine drugs act as antagonists or partial agonists at central serotonin receptors. Serotonin in platelets decreases and urinary serotonin increases during the acute phase of a migraine attack. Depletion of serotonin by reserpine may precipitate migraine. The headache and other manifestations of migraine may thus reflect a disorder of central serotonergic neurotransmission. A link between neuronal initiation and trigeminovascular-mediated pain may be calcitonin gene-related peptide (CGRP), a potent vasodilator present in increased concentrations in venous blood during migraine and cluster headache, and at decreased levels after the administration of serotonin receptor agonists such as sumatriptan.
Clinical Findings A. MIGRAINE WITH AURA (CLASSIC MIGRAINE) Classic migraine headache is preceded by transient neurologic symptoms—the aura. The most common auras are visual alterations, particularly hemianopic field defects and scotomas and scintillations that enlarge and spread peripherally (Figure 2–12). A throbbing unilateral headache ensues (Figure 2–13) with or following these prodromal features. The frequency of headache varies, but more than 50% of patients experience no more than one attack per week. The duration of episodes is greater than 2 hours and less than 1 day in most patients. Remissions are common during the second and third trimesters of pregnancy and after menopause. Especially in the elderly, prodromal symptoms may occur without headache (migraine equivalents). Although hemicranial pain is a hallmark of classic migraine, headaches can also be bilateral. Bilateral headache, therefore, does not exclude the diagnosis of migraine, nor does an occipital location—a characteristic commonly attributed to tension headaches. During the headache, prominent associated symptoms include nausea, vomiting, photophobia, phonophobia, irritability, osmophobia, and lassitude. Uncommonly, migraines are associated with frank neurologic deficits that accompany, or persist beyond, resolution of the pain phase. These may include hemiparesis, hemisensory loss, speech dysfunction, or visual disturbance. Vasomotor and autonomic symptoms are frequent; lightheadedness, vertigo, ataxia, or altered consciousness may represent vertebrobasilar ischemia. All these phenomena may be distinguished from stroke both by their gradual onset (“migrainous march”) and spontaneous resolution. Stroke may very exceptionally occur as a consquence of migraine alone.
HEADACHE & FACIAL PAIN / 87
0
15
30
Time (min)
Figure 2–12. Successive maps of scintillating scotoma to show the evolution of fortification figures and associated scotoma in a patient with classic migraine. As the fortification moves laterally, a region of transient blindness remains. B. MIGRAINE WITHOUT AURA (COMMON MIGRAINE) The common migraine headache lacks the classic aura, is usually bilateral and periorbital, and is seen more frequently in clinical practice. The pain may be described as throbbing. As the pain persists, associated cervical
muscle contraction can compound the symptoms. Scalp tenderness is often present during the episode. Vomiting may occasionally terminate the headache. A useful bedside test for both common and classic migraine is reducing headache severity by compressing the ipsilateral carotid or superficial temporal artery.
Precipitating Factors
Pain
Migraine attacks can be precipitated by certain foods (tyramine-containing cheeses; meat, such as hot dogs or bacon, with nitrite preservatives; chocolate containing phenylethylamine but not chocolate alone) and by food additives such as monosodium glutamate, a commonly used flavor enhancer. Fasting, emotion, menses, drugs (especially oral contraceptive agents and vasodilators such as nitroglycerin), and bright lights may also trigger attacks.
Treatment
Figure 2–13. Distribution of pain in migraine. Hemicranial pain (the pattern shown) is most common, but the pain can also be holocephalic, bifrontal, or unilateral frontal in distribution or, less commonly, localized to the occiput or the vertex of the skull.
Acute migraine attacks may respond to simple analgesics (eg, aspirin, acetaminophen, naprosyn). If not, they usually respond to ergot preparations or to the 5hydroxytryptamine (5-HT) agonist sumatriptan. These drugs (Table 2–5A) must be taken immediately at the onset of symptoms to be maximally effective. Rapidly absorbed forms (eg, parenteral) are superior to oral or sublingual preparations. In severe cases, subcutaneous, nasal, intramuscular, or intravenous administration is used. Unfortunately, nausea, which is a prominent feature of migraine, is also a common side effect of some drugs (particularly ergot alkaloids) so that concomitant administration of an antiemetic (eg, metoclopramide, 10 mg subcutaneously or intravenously) may be necessary. Ergot alkaloids and 5-HT agonists are potent vasoconstrictors and are contraindicated in patients
88 / CHAPTER 2 Table 2–5. Drug treatment of migraine headache. Drug A. Acute Treatment Simple analgesics Aspirin Naproxen sodium Ibuprofen Acetaminophen
Ergot preparations Ergotamine/caffeine (Cafergot)
Dihydroergotamine
Narcotic analgesics Codeine/aspirin Codeine/ acetaminophen Meperidine Butorphanol 5-HT agonists Sumatriptan (Imitrex) Rizatriptan (Maxalt) Zolmitriptan (Zomig) Naratriptan (Amerge) Almotriptan (Axert) Frovatriptan (Frova) Eletriptan (Relpax)
Route1
Strength
Recommended Dose
Comments
PO PO PO PO
325 mg 250, 375, 500 mg 300, 400, 600, 800 mg 325 mg
650–1300 mg 375–750 mg 400–800 mg 650–1300 mg
May cause gastric pain or bleeding and rebound headache if used frequently
PO
1/100 mg
2–6 tablets; max. 10 per week
May cause nausea and vomiting; contraindicated by pregnancy or coronary or peripheral vascular disease
PR
2/100 mg
1 4–2 suppositories;
/
IM, SC, IV NS
1 mg/mL 4 mg/1 mL (2 mg/treatment)
max. 5 per week 1–2 mg IM or SC; Use dihydroergotamine with 0.75–1.25 mg IV metoclopramide (see below) 1 spray to each nostril repeated in 15 minutes
PO PO
15, 30, 60/325 mg 7.5, 15, 30, 60/300 mg
30–120 mg codeine 30–120 mg codeine
PO, IM NS
50, 100 mg 10 mg/mL (1 mg/spray)
50–200 mg 1 spray every 3–4 hours as needed
NS PO SC PO PO PO PO PO PO
5, 20 mg/spray 25, 50, 100 mg 6 mg 5, 10 mg 2.5, 5 mg 1, 2.5 mg 6.25, 12.5 mg 2.5 mg 20, 40 mg
40 mg/24 hours 200 mg/24 hours 12 mg 30 mg/24 hours 10 mg/24 hours 5 mg/24 hours 25 mg/24 hours 7.5 mg/24 hours 80 mg/24 hours
Other agents Isometheptene/ PO 65/100/325 mg dichloralphenazone/ acetaminophen (Midrin) Caffeine/butalbital/ PO 40/50/325 mg aspirin (Fiorinal) Prochlorperazine PR, IM, IV 2.5/10/10 mg B. Prophylactic Treatment Antiinflammatory agents Aspirin PO Naproxen sodium PO
325 mg 275, 550 mg
10% incidence nausea, vomiting; contraindicated by pregnancy or coronary or peripheral vascular disease, and with monoamine oxidase inhibitors
2–5 capsules
1–2 tablets or capsules 2.5–10 mg
650 mg bid 500–825 mg bid
Can cause hypotension and druginduced dystonia
May cause gastric pain or bleeding
(continued)
HEADACHE & FACIAL PAIN / 89 Table 2–5. Drug treatment of migraine headache. (continued) Drug
Route1
Tricyclic antidepressants Amitriptyline2 PO Nortriptyline Protriptyline Doxepin
PO PO PO
β-Receptor antagonists Propranolol PO
Strength 10, 25, 50, 75, 100, 150 mg 10, 25, 50, 75 mg 5, 10 mg 10, 25, 30, 75, 100, 150 mg
Recommended Dose 10–175 mg hs 10–150 mg hs 5–40 mg qhs 10–150 mg hs
May cause dry mouth, urinary retention, and sedation; contraindicated in glaucoma or prostatism
PO (long acting) PO PO PO PO
10, 20, 40, 60, 80, 90 mg 60, 80, 120, 160 mg
60–320 mg qd
40, 80, 120, 160 mg 50, 100 mg 10, 20 mg 50, 100 mg
40–240 mg qd 50–200 mg bid 10–30 mg bid 50–200 mg qd
Ergot alkaloids Methergine
PO
0.2 mg
0.2–0.4 mg tid
Occurrence of retroperitoneal fibrosis with urethral obstruction and mediastinal fibrosis, although uncommon, should be monitored with creatinine, ultrasonography, or intravenous urograms, and chest x-rays every 6 months; a drug holiday every 6 months is prudent
Cyproheptadine
PO
4 mg
4–8 mg tid
Drowsiness common early in treatment
Anticonvulsants Phenytoin Valproic acid Topiramate Gabapentin
PO PO PO PO
100 mg 250, 500 mg 15, 25, 100, 200 mg 100, 300, 400, 600, 800 mg
200–400 mg qd 250–1000 mg bid 50–100 mg qd 900–2400 mg qd
40, 80, 120 mg 240 mg
80–160 mg tid 240 mg qd-bid
20 mg 5, 10 mg
20–40 mg tid 5–15 mg/d
Nadolol Atenolol Timolol Metoprolol
Calcium channel antagonists Verapamil PO PO (long acting) Nicardipine PO Flunarizine PO C. Other Agents Prochlorperazine Hydroxyzine Metoclopramide
PO, IM, IV 2.5–10 mg IM 25–100 mg PO, IV, SC 10 mg
20–160 mg bid
Comments
Listed in descending order of efficacy; symptomatic bradycardia may occur at high doses; contraindicated in asthma and congestive heart failure; not to be used with calcium blockers
Contraindicated by severe left ventricular dysfunction, hypotension, sick sinus syndrome without artificial pacemaker, or second- or third-degree AV nodal block; constipation is most common side effect; not for use with β-blockers
Adjunct to treatment; improves enteric drug absorption and reduces nausea; dystonia and akathisia may occur and respond to IV benadryl
1 PO, oral; SL, sublingual; PR, rectal; IM, intramuscular; IV, intravenous; SC, subcutaneous; NS, nasal spray; bid, twice daily; hs, at bedtime; qd, every day. 2 Other tricyclic agents such as imipramine and desipramine may also be used, are available in similar strengths, and are prescribed in similar doses.
90 / CHAPTER 2 with significant hypertension or cardiac disease. Established migraine headaches may respond to dihydroergotamine, triptans, or narcotic analgesics (eg, meperidine, 100 mg intramuscularly). Five classes of drugs have prophylactic effects in migraine: beta blockers, tricyclic antidepressants, anticonvulsants, calcium channel blockers, and ergot alkaloids (Table 2–5B). Prophylactic treatment is indicated for patients who have frequent headaches (more than one per week), acute attacks that are difficult to manage, or those for whom the ergot alkaloids or triptans used for acute treatment are poorly tolerated or contraindicated. Three structurally unrelated agents—propranolol, amitriptyline, and valproic acid—are the mainstays of therapy. Each is effective in a substantial fraction of patients, and patients refractory to one agent may respond to another. The initial choice of medication is usually influenced by consideration of clinical side effects and the patient’s other medical conditions (eg, hypertension, asthma). Propranolol, imipramine, and amitriptyline may be sedating, especially at the onset of treatment. The β-adrenergic-receptor-blocking properties of propranolol often preclude its use in patients with congestive heart failure, asthma, or insulin-dependent diabetes. It may also be associated with depression, hypotension, exercise intolerance, and impotence. The anticholinergic actions of amitriptyline may complicate glaucoma and prostatism. Valproic acid should be introduced gradually as nausea can be a problem; it is also particularly contraindicated in pregnancy. Calcium channel antagonists such as verapamil or nicardipine are also efficacious in the prophylactic treatment of migraine. Drugs available in other countries or approved in the United States only for other indications include nimodipine and flunarizine; however, both common and classic migraine respond to these drugs. As discussed above, potential side effects should be taken into account in the choice of therapy. Verapamil, which has pronounced effects on cardiac and gastrointestinal calcium channels, may exacerbate atrioventricular, nodal heart block and congestive heart failure and frequently causes constipation. Nimodipine, which is more selective for vascular smooth muscle, is associated with a higher incidence of headache, lightheadedness, hypotension, and peripheral edema. It should not be used in conjuction with β-blockers. Nifedipine is ineffective. Selective serotonin reuptake inhibitors have not been shown to be efficacious. Migraine during pregnancy should be treated only with opiates, eg, meperidine 100–150 mg orally, as all other pharmacologic agents raise concerns regarding teratogenicity or complications of pregnancy.
ANALGESIC WITHDRAWAL HEADACHE
A common, frequently unsuspected, cause of intractable headache is overuse of analgesics. The patient, in futile attempts at relief, takes increasing amounts of medications (both prescription and over-the-counter drugs). When the high blood levels drop, even slightly, the headache rebounds; the result is daily, virtually constant, atypical headache, which may be superimposed on an underlying migraine pattern. Caffeine-containing analgesics are particularly responsible. The patient should be abruptly withdrawn from all such medications and caffeine. After a few weeks of drug withdrawal symptoms the underlying, usually less severe, headache pattern will reveal itself and can be more appropriately treated. Headaches during withdrawal can be managed with oral triptans or parenteral dihydroergotamine if needed.
CLUSTER HEADACHE Cluster headache is a common headache syndrome seen much more frequently in men than in women. Cluster headaches characteristically begin at a later age than does migraine, with a mean age at onset of 25 years. There is rarely a family history of such headaches. The syndrome presents as clusters of brief, very severe, unilateral, constant nonthrobbing headaches that last from a few minutes to less than 2 hours. Unlike migraine headaches, cluster headaches are always unilateral, and usually recur on the same side in any given patient. The headaches commonly occur at night, awakening the patient from sleep, and recur daily, often at nearly the same time of day, for a cluster period of weeks to months. Between clusters, the patient may be free from headaches for months or years. Functional MRI imaging during attacks has shown activation of the ipsilateral hypothalamic gray. The headache may begin as a burning sensation over the lateral aspect of the nose or as a pressure behind the eye (Figure 2–14). Ipsilateral conjunctival injection, lacrimation, nasal stuffiness, and Horner syndrome are commonly associated with the attack (Figure 2–15). Episodes are often precipitated by the use of alcohol or vasodilating drugs, especially during a cluster siege. At the onset of a headache cluster, treatment involves measures both to abort the acute attack and to prevent subsequent ones. Acute relief of pain within minutes may be achieved by sumatriptan (Table 2–5A), 100% oxygen (8–10 L/min for 10–15 minutes), or dihydroergotamine (Table 2–5A). Several drugs used in the treatment of migraine (see Table 2–5), including 5-HT agonists, ergotamine, dihydroergotamine, methysergide, and calcium channel antagonists are also useful for preventing recurrent symptoms during an active bout of cluster headache. The most widely used is verapamil sustained-release (240–480 mg/d). Ergotamine rectal suppositories or
HEADACHE & FACIAL PAIN / 91
Pain Ptosis, miosis Tearing Nasal stuffiness and discharge
Figure 2–14. Distribution of symptoms and signs in cluster headache. subcutaneous dihydroergotamine at bedtime may be especially helpful for nocturnal headaches. Dramatic improvement can be seen with administration of prednisone at the beginning of a cluster cycle: 40–80 mg/d orally for 1 week, discontinued by tapering the dose over the following week. Pain may resolve within hours, and most patients who respond do so within 2 days. Alternatively, lithium carbonate or lithium citrate syrup, 300 mg orally one to three times daily, is highly effective in many cases. Serum lithium levels should be measured at weekly intervals for the first several weeks
and should be maintained below 1.2 meq/L to reduce the likelihood of adverse effects (nausea, diarrhea, polyuria, renal failure, hypothyroidism, tremor, dysarthria, ataxia, myoclonus, and seizures). Chronic rather than episodic cluster headaches may respond dramatically to indomethacin, 25 mg three times daily. A bilateral variant, hypnic headache, lacking the autonomic components, occurs in the elderly. It is reponsive to lithium.
TENSION-TYPE HEADACHE Tension headache is the term used to describe chronic headaches of inapparent cause that lack features characteristic of migraine or cluster headache. The underlying pathophysiologic mechanism is unknown, and tension is unlikely to be primarily responsible. Contraction of neck and scalp muscles, which has also been proposed as the cause, is probably a secondary phenomenon. In its classic form (Figure 2–16), tension headache is a chronic disorder that begins after age 20. It is characterized by frequent (often daily) attacks of nonthrobbing, bilateral occipital head pain that is not associated with nausea, vomiting, or prodromal visual disturbance. The pain is sometimes likened to a tight band around the head. Women are more commonly affected than men. Although tension headache and migraine have been traditionally considered distinct disorders, many patients have headaches that exhibit features of
Pain
Pain and spasm
Figure 2–15. Right ptosis during acute cluster
Figure 2–16. Distribution of symptoms and signs in
headache.
tension headache.
92 / CHAPTER 2 both. Thus, some patients who are classified as having tension headaches experience throbbing headaches, unilateral head pain, or vomiting with attacks. In consequence, it may be more accurate to view tension headache and migraine as representing opposite poles of a single clinical spectrum. Drugs used in the treatment of tension headache include many of the same agents used for migraine (see Table 2–5). Acute attacks may respond to aspirin, other nonsteroidal antiinflammatory drugs, acetaminophen, ergotamine, or dihydroergotamine. For prophylactic treatment, amitriptyline or imipramine are often effective, and propranolol is useful in some cases. Selective serotonin reuptake inhibitors (eg, sertraline or fluoxetine) are not useful. Although many patients respond to benzodiazepines such as diazepam, 5–30 mg/d orally, or chlordiazepoxide, 10–75 mg/d orally, these drugs should be used sparingly because of their addictive potential. Psychotherapy, physical therapy, and relaxation techniques can provide additional benefit in selected cases.
ICE PICK PAIN Very brief, sharp, severe pains located in the scalp outside of the trigeminal distribution are named by their defining characteristic as “ice pick pains.” They may be single or repetitive or occur in clusters, either at a single point or scattered over the scalp. The pains are electriclike jabs maximal in intensity in less than a second and then resolving rapidly; they are severe enough to cause involuntary flinching. They are more common in migraine and cluster patients, but occur in some headache-free individuals as well. Patients frequently seek medical attention because of the intensity of the pain. If the bouts of pain are repetitive, treatment may be indicated; the syndrome responds to indomethacin (25–50 mg three times daily).
CERVICAL SPINE DISEASE Injury or degenerative disease processes involving the upper neck can produce pain in the occiput or referred to the orbital regions. The most important source of discomfort is irritation of the second cervical nerve root. In the lower cervical spine, disk disease or abnormalities of the articular processes refer pain to the ipsilateral arm or shoulder, not to the head. Cervical muscle spasm may occur, however. Acute pain of cervical origin is treated with immobilization of the neck (eg, using a soft collar) and analgesics or antiinflammatory drugs.
SINUSITIS Acute sinusitis can produce pain and tenderness localized to the affected frontal or maxillary sinus areas. In-
flammation in the ethmoidal or sphenoidal sinuses produces a deep midline pain behind the nose. Sinusitis pain is increased by bending forward and by coughing or sneezing. Tenderness and accentuation of pain on percussion over the frontal or maxillary area are present on examination. Sinusitis is treated with vasoconstrictor nose drops (eg, phenylephrine, 0.25%, instilled every 2–3 hours), antihistamines, and antibiotics. In refractory cases, sinus drainage may be necessary. Patients who complain of chronic sinus headache rarely have recurrent inflammation of the sinuses; they are much more likely to have migraine or tension headaches.
DENTAL DISEASE Temporomandibular joint dysfunction is a poorly defined syndrome that is characterized by preauricular facial pain, limitation of jaw movement, tenderness of the muscles of mastication, and “clicking” of the jaw with movement. Symptoms are often associated with malocclusion, bruxism, or clenching of the teeth, and may result from spasm of the masticatory muscles. Some patients benefit from local application of heat, jaw exercises, nocturnal use of a bite guard, or nonsteroidal antiinflammatory drugs. Infected tooth extraction sites can also give rise to pain, which is characteristically constant, unilateral, and aching or burning in character. Although radiologic studies may be normal, injection of a local anesthetic at the extraction site relieves the symptoms. Treatment is with jaw bone curettage and antibiotics.
REFERENCES Aurora SK, Welch KM: Migraine: imaging the aura. Curr Opin Neurol 2000;13:273–276. Brew BJ, Miller J: Human immunodeficiency virus-related headache. Neurology 1993;43:1098–1100. Broadley SA, Fuller GN: Lumbar puncture needn’t be a headache. BMJ 1997;315:1324–1325. Caselli RJ, Hunder GG: Giant cell (temporal) arteritis. Neurol Clin 1997;15:893–902. DeAngelis LM: Brain tumors. N Engl J Med 2001;344:114–123. Edlow JA, Caplan LR: Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 2000;342:29–36. Forsyth PA, Posner JB: Headaches in patients with brain tumors: a study of 111 patients. Neurology 1993;43:1678–1683. Friedman DI: Pseudotumor cerebri. Neurosurg Clin N Am 1999;10:609–621. Friedman DI et al: Diagnostic criteria for idiopathic intracranial hypertension. Neurology 2002;59:1492–1495. Goadsby PJ et al: Migraine–current understanding and treatment. N Engl J Med 2002;346:257–270. Hunder GG: Giant cell arteritis and polymyalgia rheumatica. Med Clin North Am 1997;81:195–219.
HEADACHE & FACIAL PAIN / 93 Katusic S et al: Incidence and clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945–1984. Ann Neurol 1990;27:89–95. Kelly AM: Migraine: pharmacotherapy in the emergency department. West J Med 2000;173:189–193. Kost RG, Straus SE: Postherpetic neuralgia—pathogenesis, treatment, and prevention. N Engl J Med 1996;335:32–42. Lance JW, Goadsby PJ: Mechanism and Management of Headache, 6th ed. Butterworth-Heinemann, 1998. May A, Goadsby PJ: The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 1999;19:115–127. Pascual J, Berciano J: Experience in the diagnosis of headaches that start in elderly people. J Neurol Neurosurg Psychiatry 1994;57:1255–1257.
Raskin NH: Chemical headaches. Annu Rev Med 1981;32:63–71. Raskin NH: Headache, 2nd ed. Churchill Livingstone, 1988. Pringsheim T: Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function. Can J Neurol Sci 2002;29:33–40. Rushton JG, Stevens JC, Miller RH: Glossopharyngeal (vagoglossopharyngeal) neuralgia: a study of 217 cases. Arch Neurol 1981;38:201–205. Schwartz BS et al: Epidemiology of tension-type headache. JAMA 1998;279:381–383. Solomon S, Cappa KG: The headache of temporal arteritis. J Am Geriatr Soc 1987;35:163–165. Tomsak RL: Ophthalmologic aspects of headache. Med Clin North Am 1991;75:693–706. Weiller C et al: Brainstem activation in spontaneous human migraine attacks. Nat Med 1995;1:658–660. Woods RP, Iacoboni M, Mazziotta JC: Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994;331:1689–1692.
3
Disorders of Equilibrium
CONTENTS Approach to diagnosis, 95 History, 101 General physical examination, 102 Neurologic examination, 102 Investigative studies, 106 Peripheral vestibular disorders, 107 Benign positional vertigo, 107 Ménière disease, 108 Acute peripheral vestibulopathy, 109 Otosclerosis, 110 Head trauma, 110 Cerebellopontine angle tumor, 110 Toxic vestibulopathies, 111
Acoustic neuropathy, 112 Cerebellar & central vestibular disorders, 112 Acute disorders, 113 Drug intoxication, 113 Wernicke encephalopathy, 113 Vertebrobasilar ischemia & infarction, 113 Cerebellar hemorrhage, 115 Inflammatory disorders, 115 Chronic disorders, 116 Multiple sclerosis, 116 Alcoholic cerebellar degeneration, 116
Phenytoin-induced cerebellar degeneration, 117 Hypothyroidism, 117 Paraneoplastic cerebellar degeneration, 118 Autosomal dominant spinocerebellar ataxias, 118 Friedreich ataxia, 120 Ataxia-telangiectasia, 121 Wilson disease, 121 Creutzfeldt-Jakob disease, 121 Posterior fossa tumors, 122 Posterior fossa malformations, 123 Sensory ataxias, 124
KEY CONCEPTS Cerebellar hemorrhage and infarction produce disorders of equilibrium that require urgent diagnosis, because surgical evacuation of the hematoma or infarct can prevent death from brainstem compression.
Disorders of equilibrium can be produced by disorders that affect vestibular pathways, the cerebellum, or sensory pathways in the spinal cord or peripheral nerves. Disorders of equilibrium present with one or both of two cardinal symptoms: vertigo—an illusion of bodily or environmental movement, or ataxia— incoordination of limbs or gait.
94 Copyright © 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
DISORDERS OF EQUILIBRIUM / 95
APPROACH TO DIAGNOSIS Equilibrium is the ability to maintain orientation of the body and its parts in relation to external space. It depends on continuous visual, labyrinthine, and somatosensory (proprioceptive) input and its integration in the brainstem and cerebellum. Disorders of equilibrium result from diseases that affect central or peripheral vestibular pathways, the cerebellum, or sensory pathways involved in proprioception. Such disorders usually present with one of two clinical problems: vertigo or ataxia. 1. VERTIGO Vertigo is the illusion of movement of the body or the environment. It may be associated with other symptoms, such as impulsion (a sensation that the body is being hurled or pulled in space), oscillopsia (a visual illusion of moving back and forth), nausea, vomiting, or gait ataxia.
Distinction Between Vertigo & Other Symptoms Vertigo must be distinguished from nonvertiginous dizziness, which includes sensations of light-headedness, faintness, or giddiness not associated with an illusion of movement. In contrast to vertigo, these sensations are produced by conditions that impair the brain’s supply of blood, oxygen, or glucose—eg, excessive vagal stimulation, orthostatic hypotension, cardiac arrhythmias, myocardial ischemia, hypoxia, or hypoglycemia—and may culminate in loss of consciousness (syncope; see Chapter 8).
Differential Diagnosis A. ANATOMIC ORIGIN The first step in the differential diagnosis of vertigo is to localize the pathologic process in the peripheral or central vestibular pathways (Figure 3–1). Peripheral vestibular lesions affect the labyrinth of the inner ear or the vestibular division of the acoustic (VIII) nerve. Central lesions affect the brainstem vestibular nuclei or their connections. Rarely, vertigo is of cortical origin, occurring as a symptom associated with complex partial seizures. B. SYMPTOMS Certain characteristics of vertigo, including the presence of any associated abnormalities, can help differentiate between peripheral and central causes (Table 3–1). 1. Peripheral vertigo tends to be intermittent, lasts
for briefer periods, and produces more distress than vertigo of central origin. Nystagmus (rhythmic oscillation of the eyeballs) is always associated with peripheral vertigo; it is usually unidirectional and never vertical (see below). Peripheral lesions commonly produce additional symptoms of inner ear or acoustic nerve dysfunction, ie, hearing loss and tinnitus. 2. Central vertigo may occur with or without nystagmus; if nystagmus is present, it can be vertical, unidirectional, or multidirectional and may differ in character in the two eyes. (Vertical nystagmus is oscillation in a vertical plane; that produced by upgaze or downgaze is not necessarily in the vertical plane.) Central lesions may produce intrinsic brainstem or cerebellar signs, such as motor or sensory deficits, hyperreflexia, extensor plantar responses, dysarthria, or limb ataxia. 2. ATAXIA Ataxia is incoordination or clumsiness of movement that is not the result of muscular weakness. It is caused by vestibular, cerebellar, or sensory (proprioceptive) disorders. Ataxia can affect eye movement, speech (producing dysarthria), individual limbs, the trunk, stance, or gait (Table 3–2).
Vestibular Ataxia Vestibular ataxia can be produced by the same central and peripheral lesions that cause vertigo. Nystagmus is frequently present and is typically unilateral and most pronounced on gaze away from the side of vestibular involvement. Dysarthria does not occur. Vestibular ataxia is gravity dependent: Incoordination of limb movements cannot be demonstrated when the patient is examined lying down but becomes apparent when the patient attempts to stand or walk.
Cerebellar Ataxia Cerebellar ataxia is produced by lesions of the cerebellum or its afferent or efferent connections in the cerebellar peduncles, red nucleus, pons, or spinal cord (Figure 3–2). Because of the crossed connection between the frontal cerebral cortex and the cerebellum, unilateral frontal disease can also occasionally mimic a disorder of the contralateral cerebellar hemisphere. The clinical manifestations of cerebellar ataxia consist of irregularities in the rate, rhythm, amplitude, and force of voluntary movements. A. HYPOTONIA Cerebellar ataxia is commonly associated with hypotonia, which results in defective posture maintenance. Limbs are easily displaced by a relatively small force and, when shaken by the examiner, exhibit an increased range of excursion. The range of arm swing during
96 / CHAPTER 3
Medial rectus
Lateral rectus
Oculomotor (III) nerve Oculomotor (III) nucleus Medial longitudinal fasciculus
Abducens (VI) nerve Fastigial nucleus of cerebellum
Flocculonodular lobe of cerebellum
Abducens (VI) nucleus
Inferior cerebellar pedicle
Vestibular (VIII) nucleus
Vestibular (VIII) nerve Semicircular canals
Vestibulospinal tracts
Figure 3–1. Peripheral and central vestibular pathways.The vestibular nerve terminates in the vestibular nucleus of the brainstem and in midline cerebellar structures that also project to the vestibular nucleus. From here, bilateral pathways in the medial longitudinal fasciculus ascend to the abducens and oculomotor nuclei and descend to the spinal cord.
walking may be similarly increased. Tendon reflexes take on a pendular quality, so that several oscillations of the limb may occur after the reflex is elicited, although neither the force nor the rate of the reflex is increased. When muscles are contracted against resistance that is then removed, the antagonist muscle fails to check the movement and compensatory muscular relaxation does not ensue promptly. This results in rebound movement of the limb.
B. INCOORDINATION In addition to hypotonia, cerebellar ataxia is associated with incoordination of voluntary movements. Simple movements are delayed in onset, and their rates of acceleration and deceleration are decreased. The rate, rhythm, amplitude, and force of movements fluctuate, producing a jerky appearance. Because these irregularities are most pronounced during initiation and termination of movement, their most obvious clinical mani-
DISORDERS OF EQUILIBRIUM / 97 Table 3–1. Characteristics of central and peripheral vertigo. Peripheral
Central
Vertigo
Often intermittent; Often constant; severe usually less severe
Nystagmus
Always present; unidirectional, never vertical
May be absent; uni- or bidirectional, may be vertical
Often present
Rarely present
Absent
Typically present
Associated findings Hearing loss or tinnitus Intrinsic brainstem signs
festations include terminal dysmetria, or “overshoot” when the limb is directed at a target, and terminal intention tremor as the limb approaches the target. More complex movements tend to become decomposed into a succession of individual movements rather than a single smooth motor act (asynergia). Movements that involve rapid changes in direction or greater physiologic complexity, such as walking, are most severely affected. C. ASSOCIATED OCULAR ABNORMALITIES Because of the cerebellum’s prominent role in the control of eye movements, ocular abnormalities are a frequent consequence of cerebellar disease. These include nystagmus and related ocular oscillations, gaze pareses, and defective saccadic and pursuit movements.
D. ANATOMIC BASIS OF DISTRIBUTION OF CLINICAL SIGNS Various anatomic regions of the cerebellum (Figure 3–3) are functionally distinct, corresponding to the somatotopic organization of their motor, sensory, visual, and auditory connections (Figure 3–4). 1. Midline lesions—The middle zone of the cerebellum—the vermis and flocculonodular lobe and their associated subcortical (fastigial) nuclei—is involved in the control of axial functions, including eye movements, head and trunk posture, stance, and gait. Midline cerebellar disease therefore results in a clinical syndrome characterized by nystagmus and other disorders of ocular motility, oscillation of the head and trunk (titubation), instability of stance, and gait ataxia (Table 3–3). Selective involvement of the superior cerebellar vermis, as commonly occurs in alcoholic cerebellar degeneration, produces exclusively or primarily ataxia of gait, as would be predicted from the somatotopic map of the cerebellum (see Figure 3–4). 2. Hemispheric lesions—The lateral zones of the cerebellum (cerebellar hemispheres) help to coordinate movements and maintain tone in the ipsilateral limbs. The hemispheres also have a role in regulating ipsilateral gaze. Disorders affecting one cerebellar hemisphere cause ipsilateral hemiataxia and hypotonia of the limbs as well as nystagmus and transient ipsilateral gaze paresis (an inability to look voluntarily toward the affected side). Cerebellar dysarthria may also occur with paramedian lesions in the left cerebellar hemisphere. 3. Diffuse disease—Many cerebellar disorders— typically toxic, metabolic, and degenerative conditions—affect the cerebellum diffusely. The clinical picture in such states combines the features of midline and bilateral hemisphere disease.
Table 3–2. Characteristics of vestibular, cerebellar, and sensory ataxia. Vestibular
Cerebellar
Sensory
Vertigo
Present
May be present
Absent
Nystagmus
Present
Often present
Absent
Dysarthria
Absent
May be present
Absent
Limb ataxia
Absent
Usually present (one limb, unilateral, legs only, or all limbs)
Present (typically legs)
Stance
May be able to stand with feet Unable to stand with feet together together; typically worse with eyes and eyes either open or closed closed
Often able to stand with feet together and eyes open but not with eyes closed (Romberg sign)
Vibratory and position sense
Normal
Normal
Impaired
Ankle reflexes
Normal
Normal
Depressed or absent
98 Superior cerebellar peduncle
Middle cerebellar peduncle
Inferior cerebellar peduncle
Dorsal thalamus 2
Red nucleus
1, 8
3 Vestibular nucleus
Ascending limb Descending limb
Decussation
Cuneate nucleus Cerebral peduncle
Trigeminal nucleus
7
Lateral reticular nucleus Inferior olivary nucleus Arcuate nucleus
4 Medial reticular nucleus
2–6
Pontine nuclei 1
Nucleus dorsalis of Clarke
Afferent tract 1 Ventral spinocerebellar Efferent tracts 2 Cerebellothalamic 3 Cerebellorubral 4 Cerebelloreticular
Afferent tract Corticopontocerebellar
Afferent tracts 1 Vestibulocerebellar 2 Cuneocerebellar 3 Nucleocerebellar 4 Reticulocerebellar 5 Olivocerebellar 6 Arcuatocerebellar 7 Dorsal spinocerebellar Efferent tract 8 Cerebellovestibular
Figure 3–2. Cerebellar connections in the superior, middle, and inferior cerebellar peduncles.The peduncles are indicated by gray shading and the areas to and from which they project by blue shading.
DISORDERS OF EQUILIBRIUM / 99 A
Anterior
B
Posterior
Vermis
Hemisphere
Lingula
Anterior lobe
Central lobule Culmen
Declive Folium vermis Posterior lobe
Tuber vermis Pyramis
Uvula Tonsil Focculonodular lobe
Nodulus
Figure 3–3. Anatomic divisions of the cerebellum in midsagittal view (A); unfolded (arrows) and viewed from behind (B).
100 / CHAPTER 3
Anterior lobe
Posterior lobe
Hemisphere
Vermis
Figure 3–4. Functional organization of the cerebellum.The view is similar to that in Figure 3–3B but is of a monkey rather than a human cerebellum.The three cerebellar homunculi represent areas to which proprioceptive and tactile stimuli project, and the stripes represent areas to which auditory and visual stimuli project.
Sensory Ataxia Sensory ataxia results from disorders that affect the proprioceptive pathways in peripheral sensory nerves, sensory roots, posterior columns of the spinal cord, or medial lemnisci. Thalamic and parietal lobe lesions are rare causes of contralateral sensory hemiataxia. Sensa-
tions of joint position and movement (kinesthesis) originate in pacinian corpuscles and unencapsulated nerve endings in joint capsules, ligaments, muscle, and periosteum. Such sensations are transmitted via heavily myelinated A fibers of primary afferent neurons, which enter the dorsal horn of the spinal cord and ascend uncrossed in the posterior columns (Figure 3–5). Proprio-
Table 3–3. Clinical patterns of cerebellar ataxia. Pattern of Involvement
Signs
Causes
Midline
Nystagmus, head and trunk titubation, gait ataxia
Tumor, multiple sclerosis
Superior vermis
Gait ataxia
Wernicke encephalopathy, alcoholic cerebellar degeneneration, tumor, multiple sclerosis
Cerebellar hemisphere
Nystagmus, ipsilateral gaze paresis, dysarthria (especially left hemisphere lesion), ipsilateral hypotonia, ipsilateral limb ataxia, gait ataxia, falling to side of lesion
Infarction, hemorrhage, tumor, multiple sclerosis
Pancerebellar
Nystagmus, bilateral gaze paresis, dysarthria, bilateral hypotonia, bilateral limb ataxia, gait ataxia
Drug intoxications, hypothyroidism, hereditary cerebellar degeneration, paraneoplastic cerebellar degeneration,Wilson disease, infectious and parainfectious encephalomyelitis, Creutzfeldt-Jakob disease, multiple sclerosis
DISORDERS OF EQUILIBRIUM / 101 ceptive information from the legs is conveyed in the medially located fasciculus gracilis, and information from the arms is conveyed in the more laterally situated fasciculus cuneatus. These tracts synapse on second-order sensory neurons in the nucleus gracilis and nucleus cuneatus in the lower medulla. The second-order neurons decussate as internal arcuate fibers and ascend in the contralateral medial lemniscus. They terminate in the ventral posterior nucleus of the thalamus, from which third-order sensory neurons project to the parietal cortex. Sensory ataxia from polyneuropathy or posterior column lesions typically affects the gait and legs in symmetric fashion; the arms are involved to a lesser extent or spared entirely. Examination reveals impaired sensations of joint position and movement in the affected limbs, and vibratory sense is also commonly disturbed. Vertigo, nystagmus, and dysarthria are characteristically absent.
Parietal cortex
Ventral posterolateral nucleus of thalamus
Mesencephalon
Pons
Medial lemniscus Upper medulla
HISTORY Symptoms & Signs A. VERTIGO True vertigo must be distinguished from a light-headed or presyncopal sensation. Vertigo is typically described as spinning, rotating, or moving, but when the description is vague, the patient should be asked specifically if the symptom is associated with a sense of movement. The circumstances under which symptoms occur may also be diagnostically helpful. Vertigo is often brought on by changes in head position. The occurrence of symptoms upon arising after prolonged recumbency is a common feature of orthostatic hypotension, and nonvertiginous dizziness related to pancerebral hypoperfusion may be immediately relieved by sitting or lying down. Such hypoperfusion states can lead to loss of consciousness, which is rarely associated with true vertigo. If the problem is identified as vertigo, associated symptoms may help to localize the site of involvement. Complaints of hearing loss or tinnitus strongly suggest a disorder of the peripheral vestibular apparatus (labyrinth or acoustic nerve). Dysarthria, dysphagia, diplopia, or focal weakness or sensory loss affecting the face or limbs indicates the likelihood of a central (brainstem) lesion. B. ATAXIA Ataxia associated with vertigo suggests a vestibular disorder, whereas numbness or tingling in the legs is common in patients with sensory ataxia. Because proprioceptive deficits may, to some extent, be compensated for by other sensory cues, patients with sensory ataxia may report that their balance is improved by watching their feet when they walk or by using a cane or the arm
Gracile nucleus (leg) Cuneate nucleus (arm) Lower medulla Cuneate fasciculus (arm) Gracile fasciculus (leg) Dorsal root ganglion cell
Cervical spinal cord
Lumbar spinal cord
Figure 3–5. Pathway mediating proprioceptive sensation.
of a companion for support. They thus find that they are much more unsteady in the dark and may experience particular difficulty in descending stairs.
Onset & Time Course Establishing the time course of the disorder may suggest its cause. Sudden onset of disequilibrium occurs with infarcts and hemorrhages in the brainstem or cerebellum (eg, lateral medullary syndrome, cerebellar hemorrhage or infarction). Episodic disequilibrium of acute onset suggests transient ischemic attacks in the basilar artery distribution, benign positional vertigo, or Ménière disease. Disequilibrium from transient ischemic attacks is usually accompanied by cranial nerve deficits, neurologic signs in the limbs, or both. Ménière
102 / CHAPTER 3 disease is usually associated with progressive hearing loss and tinnitus as well as vertigo. Chronic, progressive disequilibrium evolving over weeks to months is most suggestive of a toxic or nutritional disorder (eg, vitamin B12 or vitamin E deficiency, nitrous oxide exposure). Evolution over months to years is characteristic of an inherited spinocerebellar degeneration.
Medical History The medical history should be scrutinized for evidence of diseases that affect the sensory pathways (vitamin B12 deficiency, syphilis) or cerebellum (hypothyroidism, paraneoplastic syndromes, tumors), and drugs that produce disequilibrium by impairing vestibular or cerebellar function (ethanol, sedative drugs, phenytoin, aminoglycoside antibiotics, quinine, salicylates).
Family History A hereditary degenerative disorder may be the cause of chronic, progressive cerebellar ataxia. Such disorders include spinocerebellar degenerations, Friedreich ataxia, ataxia-telangiectasia, and Wilson disease.
GENERAL PHYSICAL EXAMINATION Various features of the general physical examination may provide clues to the underlying disorder. Orthostatic hypotension is associated with certain sensory disorders that produce ataxia—eg, tabes dorsalis, polyneuropathies—and with some cases of spinocerebellar degeneration. The skin may show oculocutaneous telangiectasia (ataxia-telangiectasia), or it may be dry, with brittle hair (hypothyroidism) or have a lemon-yellow coloration (vitamin B12 deficiency). Pigmented corneal (Kayser-Fleischer) rings are seen in Wilson disease (see Chapter 7). Skeletal abnormalities may be present. Kyphoscoliosis is typical in Friedreich ataxia; hypertrophic or hyperextensible joints are common in tabes dorsalis; and pes cavus is a feature of certain hereditary neuropathies. Abnormalities at the craniocervical junctions may be associated with Arnold-Chiari malformations or other congenital anomalies that involve the posterior fossa.
NEUROLOGIC EXAMINATION Mental Status Examination An acute confusional state with ataxia characterizes ethanol or sedative drug intoxication and Wernicke encephalopathy. Dementia with cerebellar ataxia is seen in Wilson disease, Creutzfeldt-Jakob disease, hypothyroidism, paraneoplastic syndromes, and some spinocerebellar
degenerations. Dementia with sensory ataxia suggests syphilitic taboparesis or vitamin B12 deficiency. Korsakoff amnestic syndrome and cerebellar ataxia are associated with chronic alcoholism.
Stance & Gait Observation of stance and gait is helpful in distinguishing between cerebellar, vestibular, and sensory ataxias. In any ataxic patient, the stance and gait are wide-based and unsteady, often associated with reeling or lurching movements. A. STANCE The ataxic patient asked to stand with the feet together may show great reluctance or an inability to do so. With persistent urging, the patient may gradually move the feet closer together but will leave some space between them. Patients with sensory ataxia and some with vestibular ataxia are, nevertheless, ultimately able to stand with the feet together, compensating for the loss of one source of sensory input (proprioceptive or labyrinthine) with another (visual). This compensation is demonstrated when the patient closes the eyes, eliminating visual cues. With sensory or vestibular disorders, unsteadiness increases and may result in falling (Romberg sign). With a vestibular lesion, the tendency is to fall toward the side of the lesion. Patients with cerebellar ataxia are unable to compensate for their deficit by using visual input and are unstable on their feet whether the eyes are open or closed. B. GAIT 1. The gait seen in cerebellar ataxia is wide-based, often with a staggering quality that might suggest drunkenness. Oscillation of the head or trunk (titubation) may be present. If a unilateral cerebellar hemisphere lesion is responsible, there is a tendency to deviate toward the side of the lesion when the patient attempts to walk in a straight line or circle or marches in place with eyes closed. Tandem (heel-to-toe) gait, which requires walking with an exaggerated narrow base, is always impaired. 2. In sensory ataxia the gait is also wide-based and tandem gait is poor. In addition, walking is typically characterized by lifting the feet high off the ground and slapping them down heavily (steppage gait) because of impaired proprioception. Stability may be dramatically improved by letting the patient use a cane or lightly rest a hand on the examiner’s arm for support. If the patient is made to walk in the dark or with eyes closed, gait is much more impaired. 3. Gait ataxia may also be a manifestation of conversion disorder (conversion disorder with motor symptom or deficit) or malingering. Determining this can be particularly difficult, since isolated gait ataxia without ataxia
DISORDERS OF EQUILIBRIUM / 103 of individual limbs can also be produced by diseases that affect the superior cerebellar vermis. The most helpful observation in identifying factitious gait ataxia is that such patients often exhibit wildly reeling or lurching movements from which they are able to recover without falling. In fact, recovery of balance from such awkward positions requires excellent equilibratory function.
Oculomotor (III), Trochlear (IV), Abducens (VI), & Acoustic (VIII) Nerves Abnormalities of ocular and vestibular nerve function are typically present with vestibular disease and often present with lesions of the cerebellum. (Examination of cranial nerves III, IV, and VI is discussed in more detail in Chapter 4.) A. OCULAR ALIGNMENT The eyes are examined in the primary position of gaze (looking directly forward) to detect malalignment in the horizontal or vertical plane. B. NYSTAGMUS AND VOLUNTARY EYE MOVEMENTS The patient is asked to turn the eyes in each of the cardinal directions of gaze (left, up and left, down and left, right, up and right, down and right; see Chapter 4) to determine whether gaze paresis (impaired ability to move the two eyes coordinately in any of the cardinal directions of gaze) or gaze-evoked nystagmus is present. Nystagmus—an abnormal involuntary oscillation of the eyes—is characterized in terms of the positions of gaze in which it occurs, its amplitude, and the direction of its fast phase. Pendular nystagmus has the same velocity in both directions of eye movement; jerk nystagmus is characterized by both fast (vestibular-induced) and slow (cortical) phases. The direction of jerk nystagmus is defined by the direction of the fast component. Fast voluntary eye movements (saccades) are elicited by having the patient rapidly shift gaze from one target to another placed in a different part of the visual field. Slow voluntary eye movements (pursuits) are assessed by having the patient track a slowly moving target such as the examiner’s finger. 1. Peripheral vestibular disorders produce unidirectional horizontal jerk nystagmus that is maximal on
gaze away from the involved side. Central vestibular disorders can cause unidirectional or bidirectional horizontal nystagmus, vertical nystagmus, or gaze paresis. Cerebellar lesions are associated with a wide range of ocular abnormalities, including gaze pareses, defective saccades or pursuits, nystagmus in any or all directions, and ocular dysmetria (overshoot of visual targets during saccadic eye movements). 2. Pendular nystagmus is usually the result of visual impairment that begins in infancy. C. HEARING Preliminary examination of the acoustic (VIII) nerve should include otoscopic inspection of the auditory canals and tympanic membranes, assessment of auditory acuity in each ear, and Weber and Rinne tests performed with a 256-Hz tuning fork. 1. In the Weber test, unilateral sensorineural hearing loss (from lesions of the cochlea or cochlear nerve) causes the patient to perceive the sound produced by a vibrating tuning fork placed at the vertex of the skull as coming from the normal ear. With a conductive (external or middle ear) disorder, sound is localized to the abnormal ear. 2. The Rinne test may also distinguish between sensorineural and conductive defects in the affected ear. Air conduction (tested by holding the vibrating tuning fork next to the external auditory canal) normally produces a louder sound than does bone conduction (tested by placing the base of the tuning fork over the mastoid bone). This pattern also occurs with acoustic nerve lesions but is reversed in the case of conductive hearing loss (Table 3–4). D. POSITIONAL TESTS When patients indicate that vertigo occurs with a change in position, the Nylen-Bárány or Dix-Hallpike maneuver (Figure 3–6) is used to try to reproduce the precipitating circumstance. The head, turned to the right, is rapidly lowered 30 degrees below horizontal while the gaze is maintained to the right. This process is repeated with the head and eyes turned first to the left and then straight ahead. The eyes are observed for nystagmus, and the patient is asked to note the onset, severity, and cessation of vertigo.
Table 3–4. Assessment of hearing loss. Weber Test
Rinne Test
Normal
Sound perceived as coming from midline
Air conduction > bone conduction
Sensorineural hearing loss
Sound perceived as coming from normal ear
Air conduction > bone conduction
Conductive hearing loss
Sound perceived as coming from affected ear
Bone conduction > air conduction on affected side
104 / CHAPTER 3 A
B
Figure 3–6. Test for positional vertigo and nystagmus.The patient is seated on a table with the head and eyes directed forward (A), and is then quickly lowered to a supine position with the head over the table edge, 45 degrees below horizontal.The patient’s eyes are then observed for nystagmus, and the patient is asked to report any vertigo. The test is repeated with the patient’s head and eyes turned 45 degrees to the right (B), and again with the head and eyes turned 45 degrees to the left (not shown).
Positional nystagmus and vertigo are usually associated with peripheral vestibular lesions and are most often a feature of benign positional vertigo. This is typically characterized by severe distress, a latency of several
seconds between assumption of the position and the onset of vertigo and nystagmus, a tendency for the response to remit spontaneously (fatigue) as the position is maintained, and attenuation of the response (habitu-
DISORDERS OF EQUILIBRIUM / 105 Table 3–5. Characteristics of positional nystagmus. Feature
Peripheral Lesion
Central Lesion
Vertigo
Severe
Mild
Latency
2–40 seconds
No
Fatigability
Yes
No
Habituation
Yes
No
ation) as the offending position is repeatedly assumed (Table 3–5). Positional vertigo can also occur with central vestibular disease. E. CALORIC TESTING Disorders of the vestibuloocular pathways can be detected by caloric testing. The patient is placed supine with the head elevated 30 degrees to bring the superficially situated lateral semicircular canal into the upright position. Each ear canal is irrigated in turn with cold (33°C) or warm (44°C) water for 40 seconds, with at least 5 minutes between tests. Warm water tends to produce less discomfort than cold. Caution: Caloric testing should be preceded by careful otoscopic examination, and should not be undertaken if the tympanic membrane is perforated. 1. In the normal awake patient, cold-water caloric stimulation produces nystagmus with the slow phase
toward and the fast phase away from the irrigated ear. Warm water irrigation produces the opposite response. 2. In patients with unilateral labyrinthine, vestibular nerve, or vestibular nuclear dysfunction, irrigation of the affected side fails to cause nystagmus or elicits nystagmus that is later in onset or briefer in duration than on the normal side.
Other Cranial Nerves Papilledema associated with disequilibrium suggests an intracranial mass lesion, usually in the posterior fossa, that is causing increased intracranial pressure. Optic neuropathy may be present in multiple sclerosis, neurosyphilis, or vitamin B12 deficiency. A depressed corneal reflex or facial palsy ipsilateral to the lesion (and the ataxia) can accompany cerebellopontine angle tumor. Weakness of the tongue or palate, hoarseness, or dysphagia results from lower brainstem disease.
Motor System Examination of motor function in the patient with a disorder of equilibrium should determine the pattern and severity of ataxia and disclose any associated pyramidal, extrapyramidal, or peripheral nerve involvement that might suggest a cause. The clinical features that help distinguish cerebellar disease from diseases involving these other motor systems are summarized in Table 3–6.
Table 3–6. Clinical features distinguishing cerebellar from other motor systems disorders. Cerebellar
Upper Motor Neuron1
Lower Motor Neuron1
Extrapyramidal2
Strength
Normal
Decreased
Decreased
Normal
Tone
Decreased
Increased (spastic)3
Normal
Increased (rigid)3 or decreased
Tendon reflexes
Normal
Increased3
Decreased3
Normal
Flexor
Extensor3
Flexor
Flexor
Absent
Present3 or absent
Absent Absent
Plantar responses Atrophy
Absent
Fasciculations
Absent
Absent
Present3 or absent
Tremor
Intention tremor3 or
Absent
Absent
Resting tremor3 or absent
absent Chorea or athetosis
Absent
Absent
Absent
Present3 or absent
Akinesia
Absent
Absent
Absent
Present3 or absent
Ataxia
Present3
Absent
Absent
Absent
1
Also see Chapter 5. Also see Chapter 7. 3 Most helpful diagnostic features. 2
106 / CHAPTER 3 A. ATAXIA AND DISORDERS OF MUSCLE TONE Muscle tone is assessed as discussed in Chapter 6. Truncal stability is assessed with the patient in the sitting position, and the limbs are examined individually. 1. Movement of the patient’s arm is observed as his or her finger tracks back and forth between his or her own nose or chin and the examiner’s finger. With mild cerebellar ataxia, an intention tremor characteristically appears near the beginning and end of each such movement, and the patient may overshoot the target. 2. When the patient is asked to raise the arms rapidly to a given height—or when the arms, extended and outstretched in front of the patient, are displaced by a sudden force—there may be overshoot (rebound). Impaired ability to check the force of muscular contractions can also be demonstrated by having the patient forcefully flex the arm at the elbow against resistance— and then suddenly removing the resistance. If the limb is ataxic, continued contraction without resistance may cause the hand to strike the patient at the shoulder or in the face. 3. Ataxia of the legs is demonstrated by the supine patient’s inability to run the heel of the foot smoothly up and down the opposite shin. 4. Ataxia of any limb is reflected by irregularity in the rate, rhythm, amplitude, and force of rapid successive tapping movements. 5. Hypotonia is characteristic of cerebellar disorders; with unilateral cerebellar hemispheric lesions, the ipsilateral limbs are hypotonic. 6. Extrapyramidal hypertonia (rigidity) occurs with cerebellar ataxia in Wilson disease, acquired hepatocerebral degeneration, Creutzfeldt-Jakob disease, and certain types of olivopontocerebellar degeneration. 7. Ataxia with spasticity may be seen in multiple sclerosis, posterior fossa tumors or congenital anomalies, vertebrobasilar ischemia or infarction, olivopontocerebellar degeneration, Friedreich and other hereditary ataxias, neurosyphilis, Creutzfeldt-Jakob disease, and vitamin B12 deficiency. B. WEAKNESS The pattern of any weakness should be determined. Distal neuropathic weakness can be caused by disorders that produce sensory ataxia, such as polyneuropathies and Friedreich ataxia. Paraparesis may be superimposed on ataxia in vitamin B12 deficiency, multiple sclerosis, foramen magnum lesions, or spinal cord tumors. Ataxic quadriparesis, hemiataxia with contralateral hemiparesis, or ataxic hemiparesis suggests a brainstem lesion. C. ABNORMAL INVOLUNTARY MOVEMENTS Asterixis may occur in hepatic encephalopathy, acquired hepatocerebral degeneration, or other metabolic encephalopathies. Myoclonus occurs in the same con-
ditions as asterixis and is a prominent manifestation of Creutzfeldt-Jakob disease. Chorea may be associated with cerebellar signs in Wilson disease, acquired hepatocerebral degeneration, or ataxia-telangiectasia.
Sensory System A. JOINT POSITION SENSE In patients with sensory ataxia, joint position sense is always impaired in the legs and may be defective in the arms as well. Testing is accomplished by asking the patient to detect passive movement of the joints, beginning distally and moving proximally, to establish the upper level of deficit in each limb. Abnormalities of position sense also can be demonstrated by positioning one limb and having the patient, with eyes closed, place the opposite limb in the same position.
B. Vibratory Sense Perception of vibratory sensation is frequently impaired in patients with sensory ataxia. The patient is asked to detect the vibration of a 128-Hz tuning fork placed over a bony prominence. Again, successively more proximal sites are tested to determine the upper level of the deficit in each limb or over the trunk. The patient’s threshold for appreciating the vibration is compared with the examiner’s own ability to detect it in the hand that holds the tuning fork.
Reflexes Tendon reflexes are typically hypoactive, with a pendular quality, in cerebellar disorders; unilateral cerebellar lesions produce ipsilateral hyporeflexia. Hyporeflexia of the legs is a prominent manifestation of Friedreich ataxia, tabes dorsalis, and polyneuropathies that cause sensory ataxia. Hyperactive reflexes and extensor plantar responses may accompany ataxia caused by multiple sclerosis, vitamin B12 deficiency, focal brainstem lesions, and certain olivopontocerebellar or spinocerebellar degenerations.
INVESTIGATIVE STUDIES Blood Studies Blood studies may disclose the hematologic abnormalities associated with vitamin B12 deficiency, the decreased levels of thyroid hormones in hypothyroidism, the elevated hepatic enzymes and low ceruloplasmin and copper concentrations in Wilson disease, immunoglobulin deficiency and elevated α-fetoprotein in ataxia-telangiectasia, antibodies to Purkinje cell antigens in paraneoplastic cerebellar degeneration, or genetic abnormalities associated with hereditary spinocerebellar degenerations.
DISORDERS OF EQUILIBRIUM / 107
Cerebrospinal Fluid Studies The cerebrospinal fluid (CSF) shows elevated protein with cerebellopontine angle tumors (eg, acoustic neuroma), brainstem or spinal cord tumors, hypothyroidism, and some polyneuropathies. Increased protein with pleocytosis is commonly found with infectious or parainfectious encephalitis, paraneoplastic cerebellar degeneration, and neurosyphilis. Although elevated pressure and bloody CSF characterize cerebellar hemorrhage, lumbar puncture is contraindicated if cerebellar hemorrhage is suspected. CSF VDRL is reactive in tabes dorsalis, and oligoclonal immunoglobulin G (IgG) bands may be present in multiple sclerosis or other inflammatory disorders.
Imaging The computed tomography (CT) scan is useful for demonstrating posterior fossa tumors or malformations, cerebellar infarction or hemorrhage, and cerebellar atrophy associated with degenerative disorders. Magnetic resonance imaging (MRI) provides better visualization of posterior fossa lesions, including cerebellopontine angle tumors, and is superior to CT scanning for detecting the lesions of multiple sclerosis.
Evoked Potential Testing Evoked potential testing, especially of optic pathways (visual evoked potentials), may be helpful in evaluating patients with suspected multiple sclerosis. Brainstem auditory evoked potentials may be abnormal in patients with cerebellopontine angle tumors even though CT scans show no abnormality.
Chest X-Ray & Echocardiography The chest x-ray or echocardiogram may provide evidence of cardiomyopathy associated with Friedreich ataxia. The chest x-ray may also show a lung tumor in paraneoplastic cerebellar degeneration.
Special Studies In vestibular disorders, three additional special investigations may be of help. A. AUDIOMETRY This is useful when vestibular disorders are associated with auditory impairment; such testing can distinguish conductive, labyrinthine, acoustic nerve, and brainstem disease. Tests of pure tone hearing are abnormal when sounds are transmitted through air with conductive hearing loss and when transmitted through either air or bone with labyrinthine or acoustic nerve disorders. Speech discrimination is markedly impaired with
acoustic nerve lesions, and is impaired less with disorders of the labyrinth. Speech discrimination is normal in conductive or brainstem involvement. B. ELECTRONYSTAGMOGRAPHY (ENG) This test can be used to detect and characterize nystagmus, including that elicited by caloric stimulation. C. AUDITORY EVOKED RESPONSE This test can localize vestibular disease to the peripheral vestibular pathways.
PERIPHERAL VESTIBULAR DISORDERS A list of peripheral vestibular disorders and features helpful in the differential diagnosis is presented in Table 3–7.
BENIGN POSITIONAL VERTIGO Positional vertigo occurs upon assuming a particular head position. It is usually associated with peripheral vestibular lesions but also may be due to central (brainstem or cerebellar) disease. Benign positional vertigo is the most common cause of vertigo of peripheral origin, accounting for about 30% of cases. The most frequently identified cause is head trauma, but in most instances, no cause can be determined. The pathophysiologic basis of benign positional vertigo is thought to be canalolithiasis—stimulation of the semicircular canal by debris floating in the endolymph. The syndrome is characterized by brief (seconds to minutes) episodes of severe vertigo that may be accompanied by nausea and vomiting. Symptoms may occur with any change in head position but are usually most severe in the lateral decubitus position with the affected ear down. Episodic vertigo typically continues for several weeks and then resolves spontaneously; in some cases it is recurrent. Hearing loss is not a feature. Peripheral and central causes of positional vertigo usually can be distinguished on physical examination by means of the Nylen-Bárány or Dix-Hallpike maneuver (discussed earlier; see Figure 3–6). Positional nystagmus always accompanies vertigo in the benign disorder and is typically unidirectional, rotatory, and delayed in onset by several seconds after assumption of the precipitating head position. If the position is maintained, nystagmus and vertigo resolve within seconds to minutes. If the maneuver is repeated successively, the response is attenuated. In contrast, positional vertigo of central origin tends to be less severe, and positional
108 / CHAPTER 3 Table 3–7. Differential diagnosis of peripheral vestibular disorders. Hearing Loss Conductive
Sensorineural
Other Cranial Nerve Palsies
Benign positional vertigo
−
−
−
Ménière disease
−
+
−
Acute peripheral vestibulopathy
−
−
−
Otosclerosis
+
+
−
Head trauma
±
±
±
Cerebellopontine angle tumor
−
+
±
Toxic vestibulopathy Alcohol Aminoglycosides Salicylates Quinine
− − − −
− + + +
− − − −
Acoustic (VIII) neuropathy Basilar meningitis Hypothyroidism Diabetes Paget disease of the skull (osteitis deformans)
− − − −
+ + + +
± − ± ±
nystagmus may be absent. There is no latency, fatigue, or habituation in central positional vertigo. The mainstay of treatment in most cases of benign positional vertigo of peripheral origin (canalolithiasis) is the use of repositioning maneuvers that employ the force of gravity to move endolymphatic debris out of the semicircular canal and into the vestibule, where it can be reabsorbed. In one such maneuver (Figure 3–7), the head is turned 45 degrees in the direction of the affected ear (determined clinically, as described above), and the patient reclines to a supine position, with the head (still turned 45 degrees) hanging down over the end of the examining table. The head, still hanging down, is then turned 90 degrees in the opposite direction, to 45 degrees toward the opposite ear. Next, the patient rolls to a lateral decubitus position with the affected ear up, and the head still turned 45 degrees toward the unaffected ear and hanging down. Finally, the patient turns to a prone position and sits up. Vestibulosuppressant drugs (Table 3–8) may also be useful in the acute period, and vestibular rehabilitation, which promotes compensation for vestibular dysfunction through the recruitment of other sensory modalities, may be helpful as well.
MÉNIÈRE DISEASE Ménière disease is characterized by repeated episodes of vertigo lasting from minutes to days, accompanied by
tinnitus and progressive sensorineural hearing loss. Most cases are sporadic, but familial occurrence also has been described, and may show anticipation, or earlier onset in successive generations. Some cases appear to be related to mutations in the cochlin gene on chromosome 14q12–q13. Onset is between the ages of 20 and 50 years in about three-fourths of cases, and men are affected more often than women. The cause is thought to be an increase in the volume of labyrinthine endolymph (endolymphatic hydrops), but the pathogenetic mechanism is unknown. At the time of the first acute attack, patients already may have noted the insidious onset of tinnitus, hearing loss, and a sensation of fullness in the ear. Acute attacks are characterized by vertigo, nausea, and vomiting and recur at intervals ranging from weeks to years. Hearing deteriorates in a stepwise fashion, with bilateral involvement reported in 10–70% of patients. As hearing loss increases, vertigo tends to become less severe. Physical examination during an acute episode shows spontaneous horizontal or rotatory nystagmus (or both) that may change direction. Although spontaneous nystagmus is characteristically absent between attacks, caloric testing usually reveals impaired vestibular function. The hearing deficit is not always sufficiently advanced to be detectable at the bedside. Audiometry shows low-frequency pure-tone hearing loss, however, that fluctuates in severity as well as impaired speech discrimination and increased sensitivity to loud sounds.
DISORDERS OF EQUILIBRIUM / 109 Table 3–8. Drugs used in the treatment of vertigo.
1
Drug 2
6
Antihistamines Meclizine Promethazine Dimenhydrinate
PSC 4 5
5
UT
2, 3
3
6 1
4
Figure 3–7. Repositioning treatment for benign positional vertigo resulting from canalolithiasis. In the example shown, repositioning maneuvers are used to move endolymphatic debris out of the posterior semicircular canal (PSC) of the right ear and into the utricle (UT), the larger of two membranous sacs in the vestibule of the labyrinth, where this debris can be reabsorbed.The numbers (1–6) refer to both the position of the patient and the corresponding location of debris within the labyrinth.The patient is seated and the head is turned 45 degrees to the right (1).The head is lowered rapidly to below the horizontal (2); the examiner shifts position (3); and the head is rotated rapidly 90 degrees in the opposite direction, so it now points 45 degrees to the left, where it remains for 30 seconds (4).The patient then rolls onto the left side without turning the head in relation to the body and maintains this position for another 30 seconds (5) before sitting up (6).This maneuver may need to be repeated until nystagmus is abolished.The patient must then avoid the supine position for at least 2 days. (Courtesy of Baloh, RW. Reproduced with permission from Samuels MA et al: Office Practice of Neurology. Churchill Livingstone, 1995.)
As has been noted, episodes of vertigo tend to resolve as hearing loss progresses. Treatment is with diuretics, such as hydrochlorothiazide and triamterene. The drugs listed in Table 3–8 may also be helpful during acute attacks. In persistent, disabling, drug-resistant cases, surgical procedures such as endolymphatic shunt-
Dosage1 25 mg PO q4–6h 25–50 mg PO, IM, or PR q4–6h 50 mg PO or IM q4–6h or 100 mg PR q8h
Anticholinergics Scopolamine
0.5 mg transdermally q3d
Benzodiazepines Diazepam
5–10 mg PO or IM q4–6h
Sympathomimetics Amphetamine Ephedrine
5–10 mg PO q4–6h 25 mg PO q4–6h
1 PO, orally; IM, intramuscularly; PR, rectally. Adapted from Baloh RW, Honrubia V: Clinical Neurophysiology of the Vestibular System, 2nd ed. Vol 32 of Contemporary
ing, labyrinthectomy, or vestibular nerve section are helpful.
ACUTE PERIPHERAL VESTIBULOPATHY This term is used to describe a spontaneous attack of vertigo of inapparent cause that resolves spontaneously and is not accompanied by hearing loss or evidence of central nervous system dysfunction. It includes disorders diagnosed as acute labyrinthitis or vestibular neuronitis, which are based on unverifiable inferences about the site of disease and the pathogenetic mechanism. A recent antecedent febrile illness can sometimes be identified, however. The disorder is characterized by vertigo, nausea, and vomiting of acute onset, typically lasting up to 2 weeks. Symptoms may recur, and some degree of vestibular dysfunction may be permanent. During an attack, the patient—who appears ill— typically lies on one side with the affected ear upward and is reluctant to move his or her head. Nystagmus with the fast phase away from the affected ear is always present. The vestibular response to caloric testing is defective in one or both ears with about equal frequency. Auditory acuity is normal. Acute peripheral vestibulopathy must be distinguished from central disorders that produce acute vertigo, such as stroke in the posterior cerebral circulation. Central disease is suggested by vertical nystagmus, altered consciousness, motor or sensory deficit, or dysarthria. Treatment is with a 10- to 14-day course of
110 / CHAPTER 3 prednisone, 20 mg orally twice daily, the drugs listed in Table 3–8, or both.
OTOSCLEROSIS Otosclerosis is caused by immobility of the stapes, the ear ossicle that transmits vibration of the tympanic membrane to the inner ear. Its most distinctive feature is conductive hearing loss, but sensorineural hearing loss and vertigo are also common; tinnitus is infrequent. Auditory symptoms usually begin before 30 years of age, and familial occurrence is common. Vestibular dysfunction is most often characterized by recurrent episodic vertigo—with or without positional vertigo—and a sense of positional imbalance. More continuous symptoms may also occur, and the frequency and severity of attacks may increase with time. Vestibular abnormalities on examination include spontaneous or positional nystagmus of the peripheral type and attenuated caloric responses, which are usually unilateral. Hearing loss is always demonstrable by audiometry. It is usually of mixed conductive-sensorineural character, and is bilateral in about two-thirds of patients. In patients with episodic vertigo, progressive hearing loss, and tinnitus, otosclerosis must be distinguished from Ménière disease. Otosclerosis (rather than Ménière disease) is suggested by a positive family history, a tendency toward onset at an earlier age, the presence of conductive hearing loss, or bilateral symmetric auditory impairment. Imaging studies also may be diagnostically useful. Treatment with a combination of sodium fluoride, calcium gluconate, and vitamin D may be effective. If not, surgical stapedectomy should be considered.
common tumors at this site include meningiomas and primary cholesteatomas (epidermoid cysts). Symptoms are produced by compression or displacement of the cranial nerves, brainstem, and cerebellum and by obstruction of CSF flow. Because of their anatomic relationship to the acoustic nerve (see Figure 3–8), the trigeminal (V) and facial (VII) nerves are often affected. Acoustic neuromas occur most often as isolated lesions in patients 30–60 years old, but they may also be a manifestation of neurofibromatosis. Neurofibromatosis 1 (von Recklinghausen disease) is a common autosomal dominant disorder related to mutations in the neurofibromin gene on chromosome 17q11.2. In addition to unilateral acoustic neuromas, neurofibromatosis 1 is associated with café-au-lait spots on the skin, cutaneous neurofibromas, axillary or inguinal freckles, optic gliomas, iris hamartomas, and dysplastic bony lesions. Neurofibromatosis 2 is a rare autosomal dominant disorder caused by mutations in the neurofibromin 2 gene on chromosome 22q11.1–13.1. Its hallmark is bilateral acoustic neuromas, which may be accompanied by other tumors of the central or peripheral nervous system, including neurofibromas, meningiomas, gliomas, and schwannomas.
Clinical Findings
CEREBELLOPONTINE ANGLE TUMOR
A. SYMPTOMS AND SIGNS Hearing loss of insidious onset is usually the initial symptom. Less often, patients present with headache, vertigo, gait ataxia, facial pain, tinnitus, a sensation of fullness in the ear, or facial weakness. Although vertigo ultimately develops in 20–30% of patients, a nonspecific feeling of unsteadiness is encountered more commonly. In contrast to Ménière disease, there is a greater tendency for mild vestibular symptoms to persist between attacks. Symptoms may be stable or progress very slowly for months or years. Unilateral hearing loss of the sensorineural type is the most common finding on physical examination. Other frequently noted abnormalities are ipsilateral facial palsy, depression or loss of the corneal reflex, and sensory loss over the face. Ataxia, spontaneous nystagmus, other lower cranial nerve palsies, and signs of increased intracranial pressure are less common. Unilateral vestibular dysfunction can usually be demonstrated with caloric testing.
The cerebellopontine angle is a triangular region in the posterior fossa bordered by the cerebellum, the lateral pons, and the petrous ridge (Figure 3–8). By far the most common tumor in this area is the histologically benign acoustic neuroma (also termed neurilemoma, neurinoma, or schwannoma), which typically arises from the neurilemmal sheath of the vestibular portion of the acoustic nerve in the internal auditory canal. Less
B. LABORATORY FINDINGS Audiometry shows a sensorineural pattern of deficit with high-frequency pure-tone hearing loss, poor speech discrimination, and marked tone decay. CSF protein is elevated in about 70% of patients, usually in the range of 50–200 mg/dL. The most useful diagnostic radiologic study is MRI of the cerebellopontine angle. Acoustic neuromas sometimes cause abnormalities
HEAD TRAUMA Head trauma is the most common identifiable cause of benign positional vertigo. Injury to the labyrinth is usually responsible for posttraumatic vertigo; however, fractures of the petrosal bone may lacerate the acoustic nerve, producing vertigo and hearing loss. Hemotympanum or CSF otorrhea suggests such a fracture.
DISORDERS OF EQUILIBRIUM / 111
V
Acoustic neuroma Dorsum sellae
VI
VIII VII XII
Foramen magnum (brainstem removed)
Internal auditory canal
IX, X, XI
Internal jugular vein
Transverse sinus
Posterior fossa (cerebellum removed)
Figure 3–8. Cerebellopontine angle tumor, viewed from above, with the brain removed to permit the cranial nerves and base of the skull to be seen.The tumor, a neuroma arising from the acoustic (VIII) nerve, may compress adjacent structures, including the trigeminal (V) and facial (VII) nerves, the brainstem, and the cerebellum.
of the brainstem auditory evoked potentials at a time when radiologic studies show no abnormalities.
Differential Diagnosis Acoustic neuroma must be distinguished from other cerebellopontine angle tumors, the most common being meningioma and cholesteatoma. Meningioma should be considered in patients whose initial symptoms indicate more than isolated acoustic nerve disease. Cholesteatoma is suggested by conductive hearing loss, early facial weakness, or facial twitching, with normal CSF protein. Metastatic carcinoma may also present as a lesion in the cerebellopontine angle.
Treatment Treatment is complete surgical excision. In untreated cases, severe complications may result from brainstem compression or hydrocephalus.
TOXIC VESTIBULOPATHIES Several drugs can produce vertigo by their effects on the peripheral vestibular system.
1. ALCOHOL Alcohol causes an acute syndrome of positional vertigo because of its differential distribution between the cupula and endolymph of the inner ear. Alcohol initially diffuses into the cupula, reducing its density relative to the endolymph. This difference in density makes the peripheral vestibular apparatus unusually sensitive to gravity and thus to position. With time, alcohol also diffuses into the endolymph, and the densities of cupula and endolymph equalize, eliminating the gravitational sensitivity. As the blood alcohol level declines, alcohol leaves the cupula before it leaves the endolymph. This produces a second phase of gravitational sensitivity that persists until the alcohol diffuses out of the endolymph also. Alcohol-induced positional vertigo typically occurs within 2 hours after ingesting ethanol in amounts sufficient to produce blood levels in excess of 40 mg/dL. It is characterized clinically by vertigo and nystagmus in the lateral recumbent position and is accentuated when the eyes are closed. The syndrome lasts up to about 12 hours and consists of two symptomatic phases separated by an asymptomatic interval of 1–2 hours. Other signs of alcohol intoxication, such as spontaneous nys-
112 / CHAPTER 3 tagmus, dysarthria, and gait ataxia, are caused primarily by cerebellar dysfunction. 2. AMINOGLYCOSIDES Aminoglycoside antibiotics are widely recognized ototoxins that can produce both vestibular and auditory symptoms. Streptomycin, gentamicin, and tobramycin are the agents most likely to cause vestibular toxicity, and amikacin, kanamycin, and tobramycin are associated with hearing loss. Aminoglycosides concentrate in the perilymph and endolymph and exert their ototoxic effects by destroying sensory hair cells. The risk of toxicity is related to drug dosage, plasma concentration, duration of therapy, conditions—such as renal failure—that impair drug clearance, preexisting vestibular or cochlear dysfunction, and concomitant administration of other ototoxic agents. Symptoms of vertigo, nausea, vomiting, and gait ataxia may begin acutely; physical findings include spontaneous nystagmus and the presence of Romberg sign. The acute phase typically lasts for 1 to 2 weeks and is followed by a period of gradual improvement. Prolonged or repeated aminoglycoside therapy may be associated with a chronic syndrome of progressive vestibular dysfunction. 3. SALICYLATES Salicylates, when used chronically and in high doses, can cause vertigo, tinnitus, and sensorineural hearing loss—all usually reversible when the drug is discontinued. Symptoms result from cochlear and vestibular end-organ damage. Chronic salicylism is characterized by headache, tinnitus, hearing loss, vertigo, nausea, vomiting, thirst, hyperventilation, and sometimes a confusional state. Severe intoxication may be associated with fever, skin rash, hemorrhage, dehydration, seizures, psychosis, or coma. The characteristic laboratory findings are a high plasma salicylate level (about or above 0.35 mg/mL) and combined metabolic acidosis and respiratory alkalosis. Measures for treating salicylate intoxication include gastric lavage, administration of activated charcoal, forced diuresis, peritoneal dialysis or hemodialysis, and hemoperfusion. 4. QUININE & QUINIDINE Both quinine and quinidine can produce the syndrome of cinchonism, which resembles salicylate intoxication in many respects. The principal manifestations are tinnitus, impaired hearing, vertigo, visual deficits (including disorders of color vision), nausea, vomiting, abdominal pain, hot flushed skin, and sweating. Fever, encephalopathy, coma, and death can occur in severe cases. Symptoms result from either overdosage or idiosyncratic reactions (usually mild) to a single small dose of quinine.
5. CIS-PLATINUM This antineoplastic drug causes ototoxicity in about 50% of patients. Tinnitus, hearing loss, and vestibular dysfunction are most likely to occur with cumulative doses of 3–4 mg/kg; they may be reversible if the drug is discontinued.
ACOUSTIC NEUROPATHY Involvement of the acoustic nerve by systemic disease is an uncommon cause of vertigo. Basilar meningitis from bacterial, syphilitic, or tuberculous infection or sarcoidosis can lead to compression of the acoustic and other cranial nerves, but hearing loss is a more common consequence than vertigo. Metabolic disorders associated with acoustic neuropathy include hypothyroidism, diabetes, and Paget disease.
CEREBELLAR & CENTRAL VESTIBULAR DISORDERS Many disorders can produce acute or chronic cerebellar dysfunction (Table 3–9). Several of these conditions may also be associated with central vestibular disorders, Table 3–9. Differential diagnosis of cerebellar ataxia. Acute Drug intoxications: ethanol, sedative-hypnotics, anticonvulsants, hallucinogens Wernicke encephalopathy1 Vertebrobasilar ischemia or infarction1 Cerebellar hemorrhage Inflammatory disorders Chronic Multiple sclerosis1,2 Alcoholic cerebellar degeneration Phenytoin-induced cerebellar degeneration Hypothyroidism Paraneoplastic cerebellar degeneration Hereditary spinocerebellar ataxias (SCA1–7) Friedreich ataxia2 Ataxia-telangiectasia Wilson disease Acquired hepatolenticular degeneration Creutzfeldt-Jakob disease Posterior fossa tumor1 Posterior fossa malformations 1 May also be associated with central vestibular dysfunction. 2 May also produce sensory ataxia.
DISORDERS OF EQUILIBRIUM / 113 particularly Wernicke encephalopathy, vertebrobasilar ischemia or infarction, multiple sclerosis, and posterior fossa tumors.
ACUTE DISORDERS 1. DRUG INTOXICATION Pancerebellar dysfunction manifested by nystagmus, dysarthria, and limb and gait ataxia is a prominent feature of many drug intoxication syndromes. Agents that produce such syndromes include ethanol, sedative-hypnotics (eg, barbiturates, benzodiazepines, meprobamate, ethchlorvynol, methaqualone), anticonvulsants (such as phenytoin), and hallucinogens (especially phencyclidine). The severity of symptoms is dose related; while therapeutic doses of sedatives or anticonvulsants commonly produce nystagmus, other cerebellar signs imply toxicity. Drug-induced cerebellar ataxia often is associated with a confusional state, although cognitive function tends to be spared in phenytoin intoxication. The confusional state produced by ethanol and sedative drugs is characterized by somnolence, whereas hallucinogens are more often associated with agitated delirium. In most cases, only general supportive care is necessary. The distinctive features of intoxication with each of these groups of drugs are discussed in detail in Chapter 1. 2. WERNICKE ENCEPHALOPATHY Wernicke encephalopathy (see also Chapter 1) is an acute disorder comprising the clinical triad of ataxia, ophthalmoplegia, and confusion. It is caused by thiamine (vitamin B1) deficiency and is most common in chronic alcoholics, although it may occur as a consequence of malnutrition from any cause. The major sites of pathologic involvement are the medial thalamic nuclei, mammillary bodies, periaqueductal and periventricular brainstem nuclei (especially those of the oculomotor, abducens, and acoustic nerves), and superior cerebellar vermis. Cerebellar and vestibular involvement both contribute to the ataxia. Ataxia affects gait primarily or exclusively; the legs themselves are ataxic in only about one-fifth of patients, and the arms in one-tenth. Dysarthria is rare. Other classic findings include an amnestic syndrome or global confusional state, horizontal or combined horizontal-vertical nystagmus, bilateral lateral rectus palsies, and absent ankle jerks. Caloric testing reveals bilateral or unilateral vestibular dysfunction. Conjugate gaze palsies, pupillary abnormalities, and hypothermia can also occur. The diagnosis is established by the response to administration of thiamine, which is usually given initially in a dose of 100 mg intravenously. Ocular palsies tend to be the earliest deficits to improve and typically begin to do so within hours. Ataxia, nystagmus, and
acute confusion start to resolve within a few days. Recovery from ocular palsies is invariably complete, but horizontal nystagmus may persist. Ataxia is fully reversible in only about 40% of patients; where gait returns fully to normal, recovery typically takes several weeks to months. 3. VERTEBROBASILAR ISCHEMIA & INFARCTION Transient ischemic attacks and strokes in the vertebrobasilar system are often associated with ataxia or vertigo.
Internal Auditory Artery Occlusion Vertigo of central vestibular origin with unilateral hearing loss results from occlusion of the internal auditory artery (Figure 3–9), which supplies the acoustic nerve. This vessel may originate from the basilar or anterior inferior cerebellar artery. Vertigo is accompanied by nystagmus, with the fast phase directed away from the involved side. Hearing loss is unilateral and sensorineural.
Lateral Medullary Infarction Lateral medullary infarction produces Wallenberg syndrome (Figure 3–10) and is most often caused by proximal vertebral artery occlusion. Clinical manifestations vary, depending on the extent of infarction. They typically consist of vertigo, nausea, vomiting, dysphagia, hoarseness, and nystagmus in addition to ipsilateral Horner syndrome, limb ataxia, impairment of all sensory modalities over the face, and loss of light touch Basilar artery Posterior cerebral artery Internal auditory artery
Anterior inferior cerebellar artery
Superior cerebellar artery
Vertebral artery
Posterior inferior cerebellar artery
Figure 3–9. Principal arteries of the posterior fossa.
114 / CHAPTER 3 Vestibular nuclei Cuneate/gracile nuclei
Dorsal motor nucleus of vagus nerve
Nucleus solitarius Wallenberg syndrome Inferior cerebellar peduncle Spinal tract and nucleus of trigeminal nerve Descending sympathetic tract Nucleus ambiguus Spinothalamic tract Inferior olive Hypoglossal nerve Pyramidal tract
Figure 3–10. Lateral medullary infarction (Wallenberg syndrome) showing the area of infarction (shaded) and anatomic structures affected.
and position sense in the limbs. There is also impairment of pinprick and temperature appreciation in the contralateral limbs. Vertigo results from involvement of the vestibular nuclei and hemiataxia from involvement of the inferior cerebellar peduncle.
Cerebellar Infarction The cerebellum is supplied by three arteries: the superior cerebellar, anterior inferior cerebellar, and posterior inferior cerebellar. The territory supplied by each of these vessels is highly variable, both from one individual to another and between the two sides of the cerebellum in a given patient. The superior, middle, and inferior cerebellar peduncles are typically supplied by the superior, anterior inferior, and posterior inferior cerebellar arteries, respectively. Cerebellar infarction results from occlusion of a cerebellar artery (Figure 3–11); the clinical syndromes produced can be distinguished only by the associated brainstem findings. In each case, cerebellar signs include ipsilateral limb ataxia and hypotonia. Other symptoms and signs such as headache, nausea, vomiting, vertigo, nystagmus, dysarthria, ocular or gaze palsies, facial weakness or sensory loss, and contralateral hemiparesis or hemisensory deficit may be present. Brainstem infarction or compression by cerebellar edema can result in coma and death. The diagnosis of cerebellar infarction is made by CT scan or MRI, which allows differentiation between infarction and hemorrhage; it should be obtained
Superior cerebellar artery Anterior inferior cerebellar artery Posterior inferior cerebellar artery
Figure 3–11. Arterial supply of the cerebellum, viewed from below.
DISORDERS OF EQUILIBRIUM / 115 promptly. When brainstem compression occurs, surgical decompression and resection of infarcted tissue can be lifesaving.
Paramedian Midbrain Infarction Paramedian midbrain infarction caused by occlusion of the paramedian penetrating branches of the basilar artery affects the third nerve root fibers and red nucleus (Figure 3–12). The resulting clinical picture (Benedikt syndrome) consists of ipsilateral medial rectus palsy with a fixed dilated pupil and contralateral limb ataxia (typically affecting only the arm). Cerebellar signs result from involvement of the red nucleus, which receives a crossed projection from the cerebellum in the ascending limb of the superior cerebellar peduncle. 4. CEREBELLAR HEMORRHAGE Most cerebellar hemorrhages are due to hypertensive vascular disease; less common causes include anticoagulation, arteriovenous malformation, blood dyscrasia, tumor, and trauma. Hypertensive cerebellar hemorrhages are usually located in the deep white matter of the cerebellum and commonly extend into the fourth ventricle. The classic clinical picture of hypertensive cerebellar hemorrhage consists of the sudden onset of headache, which may be accompanied by nausea, vomiting, and vertigo, followed by gait ataxia and impaired consciousness, usually evolving over a period of hours. At the time of presentation, patients can be fully alert, conSuperior colliculus
fused, or comatose. In alert patients, nausea and vomiting are often prominent. The blood pressure is typically elevated, and nuchal rigidity may be present. The pupils are often small and sluggishly reactive. Ipsilateral gaze palsy (with gaze preference away from the side of hemorrhage) and ipsilateral peripheral facial palsy are common. The gaze preference cannot be overcome by caloric stimulation. Nystagmus and ipsilateral depression of the corneal reflex may occur. The patient, if alert, exhibits ataxia of stance and gait; limb ataxia is less common. In the late stage of brainstem compression, the legs are spastic and extensor plantar responses are present. The CSF is frequently bloody, but lumbar puncture should be avoided if cerebellar hemorrhage is suspected, because it may lead to a herniation syndrome. The diagnostic procedure of choice is a CT scan. Treatment consists of surgical evacuation of the hematoma, a procedure that can be lifesaving. 5. INFLAMMATORY DISORDERS Acute inflammatory disorders of the cerebellum mediated by infection or immune mechanisms are important and often reversible causes of ataxia. Cerebellar ataxia caused by viral infection is one of the principal manifestations of St. Louis encephalitis. AIDS dementia complex and meningoencephalitis associated with varicella, mumps, poliomyelitis, infectious mononucleosis, and lymphocytic choriomeningitis can also produce cerebellar symptoms. Bacterial infection is a less Benedikt syndrome
Oculomotor nucleus Medial lemniscus
Red nucleus Substantia nigra Cerebral peduncle
Oculomotor nerve (III)
Figure 3–12. Paramedian midbrain infarction (Benedikt syndrome).The area of infarction is indicated by shading.
116 / CHAPTER 3 common cause of cerebellar ataxia; 10–20% of brain abscesses are located in the cerebellum, however, and ataxia may be a feature of Haemophilus influenzae meningitis in children. A cerebellar syndrome has been described in legionnaire’s disease, usually without clinical evidence of meningitis. Several conditions that may occur following an acute febrile illness or vaccination produce cerebellar ataxia that is assumed to be of autoimmune origin.
Acute Cerebellar Ataxia of Childhood Acute cerebellar ataxia of childhood is a syndrome characterized by severe gait ataxia that usually resolves completely within months. It generally follows an acute viral infection or inoculation. A full discussion of cerebellar ataxia in childhood is beyond the scope of this chapter.
Acute Disseminated Encephalomyelitis This immune-mediated disorder may cause demyelination and inflammatory changes in the cerebellar white matter, producing ataxia that is often associated with impaired consciousness, seizures, focal neurological signs, or myelopathy.
Fisher Variant of Guillain-Barré Syndrome Cerebellar ataxia, external ophthalmoplegia, and areflexia constitute this variant of Guillain-Barré syndrome. Symptoms develop over a few days. Ataxia primarily affects the gait and trunk, with lesser involvement of the individual limbs; dysarthria is uncommon. CSF protein may be elevated. Respiratory insufficiency occurs rarely, and the usual course is of gradual and often complete recovery over weeks to months. The ataxia is similar to that of cerebellar disease, but it is not yet known whether it arises centrally or peripherally.
CHRONIC DISORDERS 1. MULTIPLE SCLEROSIS Multiple sclerosis can produce disorders of equilibrium of cerebellar, vestibular, or sensory origin. Cerebellar signs are associated with demyelinated areas (plaques) in the white matter of the cerebellum, cerebellar peduncles, or brainstem. As is the case with other manifestations of multiple sclerosis, these signs may remit and relapse. Involvement of vestibular pathways in the brainstem produces vertigo, which may be acute in onset and sometimes positional. Vertigo, which is rarely the first symptom of multiple sclerosis, is not uncommon during the course of the disease. Gait ataxia from cerebellar involvement is a presenting
complaint in 10–15% of patients. Cerebellar signs are present in about one-third of patients on initial examination; they ultimately develop in twice that number. Nystagmus is one of the most common physical findings; it can occur with or without other evidence of cerebellar dysfunction. Dysarthria also occurs frequently. When gait ataxia occurs, it is most often cerebellar rather than sensory in origin. Ataxia of the limbs is common; it is usually bilateral and tends to affect either both legs or all four limbs. Evidence that a cerebellar disorder is due to multiple sclerosis may be found in a history of remitting and relapsing neurologic dysfunction that affects multiple sites in the central nervous system; from such associated abnormalities as optic neuritis, internuclear ophthalmoplegia, or pyramidal signs; or from laboratory investigations. CSF analysis may reveal oligoclonal bands, elevated IgG, increased protein, or a mild lymphocytic pleocytosis. Visual, auditory, or somatosensory evoked response recording can document subclinical sites of involvement. The CT scan or MRI may show areas of demyelination. It must be emphasized, however, that no laboratory finding is itself diagnostic of multiple sclerosis, and the history and neurologic examination must be primarily relied upon in arriving at such a diagnosis. Multiple sclerosis is discussed in more detail in Chapter 5. 2. ALCOHOLIC CEREBELLAR DEGENERATION A characteristic cerebellar syndrome may develop in chronic alcoholics, probably as a result of nutritional deficiency. Affected patients typically have a history of daily or binge drinking lasting 10 or more years with associated dietary inadequacy. Most have experienced other medical complications of alcoholism: liver disease, delirium tremens, Wernicke encephalopathy, or polyneuropathy. Alcoholic cerebellar degeneration is most common in men and usually has its onset between the ages of 40 and 60 years. Degenerative changes in the cerebellum are largely restricted to the superior vermis (Figure 3–13); because this is also the site of cerebellar involvement in Wernicke encephalopathy, both disorders may be part of the same clinical spectrum. Alcoholic cerebellar degeneration is usually insidious in onset; it is gradually progressive, eventually reaching a stable level of deficit. Progression over weeks to months is more common than is deterioration over years; in occasional cases, ataxia appears abruptly or is mild and stable from the onset. Gait ataxia is a universal feature and is almost always the problem that initially commands medical attention. The legs are also ataxic on heel-knee-shin testing in about 80% of patients. Commonly associated findings are distal sensory deficits in the feet and absent ankle
DISORDERS OF EQUILIBRIUM / 117 Superior vermis
Posterior
Anterior
Purkinje cell loss
Figure 3–13. Distribution of disease in alcoholic cerebellar degeneration. Midsagittal view of the cerebellum showing loss of Purkinje cells, confined largely to the superior vermis.
mis is relatively spared. Clinical features include nystagmus, dysarthria, and ataxia affecting the limbs, trunk, and gait. Polyneuropathy may be present. Symptoms are typically irreversible, but tend to stabilize when the drug is discontinued. 4. HYPOTHYROIDISM Among the neurologic disorders associated with hypothyroidism is a subacute or chronically progressive cerebellar syndrome. This condition may complicate hypothyroidism (of various causes) and is most common in middle-aged or elderly women. Symptoms evolve over a period of months to years. Systemic symptoms of myxedema usually precede the appearance of the cerebellar disorder, but patients occasionally present first with ataxia. Gait ataxia is the most prominent finding and is present in all patients; ataxia of the limbs, which is also common, may be asymmetric. Dysarthria and nystagmus occur less frequently. Patients may exhibit other neurologic disorders related to hypothyroidism, including sensorineural hearing loss, carpal tunnel syndrome, neuropathy, or myopathy.
reflexes—from polyneuropathy—and signs of malnutrition such as loss of subcutaneous tissue, generalized muscle atrophy, or glossitis. Less frequent manifestations include ataxia of the arms, nystagmus, dysarthria, hypotonia, and truncal instability. CT scan or MRI may show cerebellar atrophy (Figure 3–14), but this is a nonspecific finding that can be encountered in any degenerative disorder that affects the cerebellum. Chronic cerebellar ataxia that begins in adulthood and primarily affects gait can also occur in hypothyroidism, paraneoplastic syndromes, idiopathic cerebellar degenerations, and anomalies at the craniocervical junction such as Arnold-Chiari malformation. The possibility of hypothyroidism or systemic cancer, which may be treatable, should be investigated with thyroid function tests, chest x-ray, and, in women, breast and pelvic examinations. No specific treatment is available for alcoholic cerebellar degeneration. Nonetheless, all patients with this diagnosis should receive thiamine because of the apparent role of thiamine deficiency in the pathogenesis of Wernicke encephalopathy, a closely related syndrome. Abstinence from alcohol, combined with adequate nutrition, leads to stabilization in most cases. 3. PHENYTOIN-INDUCED CEREBELLAR DEGENERATION Chronic therapy with phenytoin, often with drug levels in the toxic range, may cause cerebellar degeneration that affects the cerebellar hemispheres and inferior and posterior vermis most severely, while the superior ver-
Figure 3–14. CT scan in alcoholic cerebellar degeneration, showing marked atrophy of the cerebellar vermis with relative sparing of the cerebellar hemispheres. (Courtesy of A Gean.)
118 / CHAPTER 3 Laboratory studies show decreased blood levels of thyroid hormones, elevated thyroid-stimulating hormone (TSH), and often increased CSF protein. Replacement therapy with levothyroxine, 25–50 µg, increased gradually to 100–200 µg/d orally, usually produces definite but incomplete improvement. 5. PARANEOPLASTIC CEREBELLAR DEGENERATION Cerebellar degeneration can also occur as a remote effect of systemic cancer. Lung cancer (especially smallcell), ovarian cancer, Hodgkin disease, and breast cancer are the most commonly associated neoplasms. Paraneoplastic degeneration affects the cerebellar vermis and hemispheres diffusely. The pathogenetic mechanism in many cases appears to involve antibodies to tumor cell antigens that cross-react with cerebellar Purkinje cells. Cerebellar symptoms may appear before or after the diagnosis of systemic cancer and typically develop over months. Although the disorder usually progresses steadily, it may stabilize; remission has been described with treatment of the underlying neoplasm. Gait and limb ataxia are characteristically prominent, and dysarthria occurs in most cases. The limbs may be affected asymmetrically. Nystagmus is rare. Paraneoplastic involvement of other regions of the nervous system may produce associated dysphagia, dementia, memory disturbance, pyramidal signs, or neuropathy. Anti-Purkinje cell antibodies, such as anti-Yo (ovarian and breast cancer), or antinuclear antibodies, such as anti-Hu (small-cell lung cancer) and anti-Ri (breast cancer), can sometimes be de-
tected in the blood (Table 3–10). The CSF may show a mild lymphocytic pleocytosis or elevated protein. Treatment may include removal of the underlying tumor or immunosuppression. The diagnosis of paraneoplastic cerebellar degeneration is most difficult when the neurologic symptoms precede the discovery of underlying cancer. The frequent occurrence of dysarthria and dysphagia helps to distinguish this condition from the cerebellar syndromes produced by chronic alcoholism or hypothyroidism. Ataxia of the arms also suggests that alcohol is an unlikely cause. Wernicke encephalopathy should always be considered because of the susceptibility of patients with cancer to malnutrition. 6. AUTOSOMAL DOMINANT SPINOCEREBELLAR ATAXIAS The hereditary spinocerebellar degenerations (Table 3–11) are a group of inherited disorders characterized by slowly progressive cerebellar ataxia that affects gait early and severely and may eventually confine the patient to bed. These disorders show considerable clinical variability, even within a given family. Most autosomal dominant forms, termed spinocerebellar ataxias or SCAs, begin in adulthood and show anticipation, in which the age at onset decreases, the disease severity increases, or both, in successive generations. Autosomal dominant spinocerebellar ataxia is genetically heterogeneous. The best characterized gene defects are expanded CAG trinucleotide repeats coding for polyglutamine tracts in proteins without known function (ataxins), and in the α1A-subunit of the P/Qtype calcium channel, which is found on nerve termi-
Table 3–10. Antineuronal autoantibodies in paraneoplastic syndromes. Antigen Syndrome
Hu
Limbic encephalitis
+
Brainstem encephalitis
+
Cerebellar degeneration
+
Yo
Ri
Tr
VGCC1
+ +
+
+
+
VGKC3
+ +
+ + +
Neuromyotonia
1
Ma2 mGluR12 +
Stiff-person syndrome
Lambert-Eaton syndrome
Ma1
+
Opsoclonus/myoclonus
Sensory neuronopathy
Amphiphysin
+
Voltage-gated calcium channel, P/Q type. Metabotropic glutamate receptor, type 1. 3 Voltage-gated potassium channel. Adapted from Darnell RB, Posner JB: Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543–1554. 2
Table 3–11. Genetic and clinical features of hereditary spinocerebellar ataxias. Disease
Gene
Protein
Gene Defect
Syndrome
Autosomal recessive FA1
FRDA1
Frataxin
GAAn2
3
Autosomal dominant SCA 14
SCA1
Ataxin-1
CAGn
ADCA I5
SCA 2
SCA2
Ataxin-2
CAGn
ADCA I
SCA 3/MJD6
SCA3
Ataxin-3
CAGn
ADCA I
SCA 4
SCA4
Unknown
Unknown
ADCA I
SCA 5
SCA5
Unknown
Unknown
ADCA III
SCA 6
CACNL1A4
Ca channel7
CAGn
ADCA III
SCA 7
SCA7
Ataxin-7
CAGn
ADCA II
SCA 8
SCA8
Unknown
CTGn
ADCA I
SCA 10
SCA10
Ataxin-10
ATTCTn
ADCA III
SCA 11
SCA11
Unknown
Unknown
ADCA III
SCA 12
PPP2R2B
PPase28
CAGn
ADCA I
SCA 13
SCA13
Unknown
Unknown
9
SCA 14
PRKCG
PKCγ10
Missense
ADCA III
SCA 15
SCA15
Unknown
Unknown
ADCA III
SCA 16
SCA16
Unknown
Unknown
ADCA III
SCA 17
TBP
TATA-binding protein
CAGn
ADCA I
SCA18
SCA18
Unknown
Unknown
11
SCA19
SCA19
Unknown
Unknown
12
SCA20
SCA20
Unknown
Unknown
13
SCA21
SCA21
Unknown
Unknown
14
SCA22
SCA22
Unknown
Unknown
ADCA III
SCA23
SCA23
Unknown
Unknown
15
SCA + tremor
FGF14
Fibroblast growth factor-14
Missense
ADCA I
SCA25
SCA25
Unknown
Unknown
16
1
FA, Friedreich ataxia. XYZn, expanded XYZ trinucleotide repeat; VWXYZn, expanded VWXYZ pentanucleotide repeat. 3 Childhood onset, ataxia, dysarthria, pyramidal signs, neuropathy, scoliosis, cardiomyopathy, diabetes. 4 SCA, spinocerebellar ataxia. 5 ADCA I includes ataxia, dysarthria, pyramidal signs, extrapyramidal signs, ophthalmoplegia and dementia; ADCA II includes ataxia, dysarthria, and pigmentary maculopathy; ADCA III includes ataxia, dysarthria, and sometimes mild pyramidal signs. 6 MJD, Machado-Joseph disease (same as SCA3). 7 P/Q-type voltage-gated calcium channel, α -subunit. 1A 8 Protein phosphatase 2, regulatory subunit B, β isoform. 9 Childhood onset, ataxia, and mental retardation. 10 Protein kinase C, gamma subunit. 11 Ataxia, muscle atrophy, sensory deficit. 12 Ataxia, mild cognitive defect. 13 Ataxia, dysphonia, palatal tremor. 14 Ataxia, extrapyramidal signs. 15 Ataxia, tremor, dyskinesia. 16 Ataxia, sensory neuropathy. Adapted from www.neuro.wustl.edu 2
119
120 / CHAPTER 3 nals. Other types of mutations include expanded CTG trinucleotide (SCA8) and ATTCT pentanucleotide (SCA10) repeats. In many cases, the size of these expansions correlates with disease severity and inversely with age at onset. The gain-of-function mutations seen in SCAs appear to alter the properties of the mutated protein, which cannot be processed normally. The abnormally processed fragments are conjugated with ubiquitin, a protein involved in nonlysosomal degradation of defective proteins, with which they are transported to the nucleus in a complex called a proteasome. The precise relationship of this accumulation to the neurotoxicity that results from these mutations is uncertain, but intranuclear protein aggregates may interfere with nuclear function. Atrophy of the cerebellum and sometimes also of the brainstem may be apparent on CT or MRI scans (Figure 3–15). However, definitive diagnosis is by demonstrating one of the known SCA gene defects on genetic testing. There is no specific treatment for the spinocerebellar ataxias, but occupational and physical therapy and devices to assist ambulation may be helpful, and genetic counseling may be indicated. Dentatorubral pallidoluysian atrophy (DRPLA) also produces autosomal dominant cerebellar ataxia and results from a polyglutamine expansion. Because extrapyramidal features are prominent, this disorder is discussed in Chapter 7.
Figure 3–15. CT scan in spinocerebellar atrophy, showing an atrophic cerebellum and brainstem. (Courtesy of A Gean.)
7. FRIEDREICH ATAXIA Among the idiopathic degenerative disorders that produce cerebellar ataxia, Friedreich ataxia merits separate consideration because it is the most common, and because of its unique clinical and pathologic features. Unlike most of the late-onset autosomal dominant spinocerebellar ataxias discussed above, Friedreich ataxia begins in childhood. It is transmitted by autosomal recessive inheritance and is due to an expanded GAA trinucleotide repeat in a noncoding region of the frataxin gene on chromosome 9 (see Table 3–11). The recessive inheritance of Friedreich ataxia suggests a lossof-function mutation. Most affected patients are homozygous for the trinucleotide repeat expansion in the Friedreich ataxia gene, but some are heterozygous, with the repeat affecting one allele and a point mutation on the other allele. The pathologic findings are localized, for the most part, to the spinal cord. These include degeneration of the spinocerebellar tracts, posterior columns, and dorsal roots as well as depletion of the neurons in Clarke column that are the cells of origin of the dorsal spinocerebellar tracts. Large myelinated axons of peripheral nerves and cell bodies of primary sensory neurons in dorsal root ganglia are also involved.
Clinical Findings Detailed clinical evaluation of relatively large numbers of patients has allowed certain diagnostic criteria to be established (see Table 3–11). Clinical manifestations almost always appear after age 4 years and before the end of puberty, with more expanded repeats correlating with earlier onset. The initial symptom is progressive gait ataxia, followed by ataxia of all limbs within 2 years. During the same early period, knee and ankle tendon reflexes are lost and cerebellar dysarthria appears; reflexes in the arms and in some cases at the knees may be preserved. Joint position and vibration sense are impaired in the legs, typically adding a sensory component to the gait ataxia. Abnormalities of light touch, pain, and temperature sensation occur less frequently. Weakness of the legs—and less often the arms—is a later development and may be of the upper or lower motor neuron variety (or both). Extensor plantar responses usually appear during the first 5 years of symptomatic disease. Pes cavus (higharched feet with clawing of the toes caused by weakness and wasting of the intrinsic foot muscles) is a widely recognized sign, but it also may be an isolated finding in otherwise unaffected family members. It is also a classic feature of other neurologic disorders, notably certain hereditary peripheral neuropathies (eg, CharcotMarie-Tooth disease). Severe progressive kyphoscoliosis contributes to functional disability and may lead to
DISORDERS OF EQUILIBRIUM / 121 chronic restrictive lung disease. While cardiomyopathy is sometimes detectable only by echocardiography or vectorcardiography, it may result in congestive heart failure and is a major cause of morbidity and death. Other abnormalities include visual impairment (usually from optic atrophy), nystagmus, paresthesias, tremor, hearing loss, vertigo, spasticity, leg pains, and diabetes mellitus.
Differential Diagnosis Friedreich ataxia can usually be differentiated from other cerebellar and spinocerebellar degenerations (see above) by its early onset and the presence of prominent sensory impairment, areflexia, skeletal abnormalities, and cardiomyopathy. A somewhat similar disorder may result from vitamin E deficiency. Cerebellar ataxia that begins in childhood can also be caused by ataxia-telangiectasia; the clinical features that distinguish Friedreich ataxia from ataxia-telangiectasia are discussed below.
Prognosis No treatment is available, but orthopedic procedures such as tenotomy may help to correct foot deformities. Advances in antimicrobial therapy have altered the ultimate course of the disorder, so that cardiomyopathy has become more frequent and infection less frequent as a cause of death. Neurologic dysfunction typically results in the inability to walk unaided within 5 years after the onset of symptoms and in a bedridden state within 10–20 years. The average duration of symptomatic illness is about 25 years, with death occurring at a mean age of about 35 years. 8. ATAXIA-TELANGIECTASIA Ataxia-telangiectasia (also known as Louis-Bar syndrome) is an inherited autosomal recessive disorder with its onset in infancy. The disease results from mutations in the ATM gene, which has been localized to chromosome 11q22.3. Deletions, insertions, and substitutions all have been described and are presumed to represent loss-of-function mutations, consistent with the autosomal recessive inheritance of ataxia-telangiectasia. Although the abnormal gene product has not been identified, a defect in DNA repair is thought to be involved in pathogenesis. Ataxia-telangiectasia is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, and immunologic deficiency. All patients suffer from progressive pancerebellar degeneration—characterized by nystagmus, dysarthria, and gait, limb, and trunk ataxia—that begins in infancy. Choreoathetosis, loss of vibration and position sense in the legs, areflexia, and disorders of voluntary eye movement are almost universal findings. Mental deficiency is commonly observed in the second decade; oculocutaneous telangiectasia usually appears in the
teen years. The bulbar conjunctivae are typically affected first, followed by sun-exposed areas of the skin, including the ears, nose, face, and antecubital and popliteal fossae. The vascular lesions, which rarely bleed, spare the central nervous system. Immunologic impairment (decreased circulating IgA and IgE) usually becomes evident later in childhood and is manifested by recurrent sinopulmonary infections in more than 80% of patients. Other common clinical findings are progeric changes of the skin and hair, hypogonadism, and insulin resistance. The characteristic laboratory abnormalities include those related to immunologic deficiency and elevation of α-fetoprotein and carcinoembryonic antigen levels. Because the vascular and immunologic manifestations of ataxia-telangiectasia occur later than the neurologic symptoms, the condition may be confused with Friedreich ataxia, which also manifests in childhood (see above). Ataxia-telangiectasia can be distinguished by its earlier onset (before age 4 years), associated choreoathetosis, and the absence of such skeletal abnormalities as kyphoscoliosis. There is no specific treatment for ataxia-telangiectasia, but antibiotics are useful in the management of infections and x-rays should be avoided because of the abnormal cellular sensitivity to ionizing radiation in this disorder. 9. WILSON DISEASE Cerebellar symptoms may occur in Wilson disease, a disorder of copper metabolism characterized by copper deposition in a variety of tissues. Wilson disease is an inherited autosomal recessive disorder due to mutations in the ATP7B gene on chromosome 13q14.3–q21.1, which codes for the β polypeptide of a copper-transporting ATPase. Wilson disease is discussed in more detail in Chapter 7. 10. CREUTZFELDT-JAKOB DISEASE Creutzfeldt-Jakob disease is described in Chapter 1 as a prion disease that causes dementia. Cerebellar signs are present in about 60% of patients, and the patients present with ataxia in about 10% of cases. Cerebellar involvement is diffuse, but the vermis is often most severely affected. In contrast to most other cerebellar disorders, depletion of granule cells is frequently more striking than Purkinje cell loss. Patients with cerebellar manifestations of Creutzfeldt-Jakob disease usually complain first of gait ataxia. Dementia is usually evident at this time, and cognitive dysfunction always develops eventually. Nystagmus, dysarthria, truncal ataxia, and limb ataxia are all present initially in about half the patients with the ataxic form of Creutzfeldt-Jakob disease. The course is characterized by progressive dementia, myoclonus, and
122 / CHAPTER 3 extrapyramidal and pyramidal dysfunction. Death typically occurs within 1 year after onset. 11. POSTERIOR FOSSA TUMORS Tumors of the posterior fossa cause cerebellar symptoms when they arise in the cerebellum or compress it from without. The most common cerebellar tumors of childhood are astrocytomas and medulloblastomas. Metastases from primary sites outside the nervous system predominate in adults (Table 3–12). Patients with cerebellar tumors present with headache from the increased intracranial pressure or with ataxia. Nausea, vomiting, vertigo, cranial nerve palsies, and hydrocephalus are common. The nature of the clinical findings varies with the location of the tumor. Most metastases are located in the cerebellar hemispheres, causing asymmetric cerebellar signs. Medulloblastomas and ependymomas, on the other hand, tend to arise in the midline, with early involvement of the vermis and hydrocephalus. As in the case of most brain tumors, the CT scan or—especially—MRI is extremely useful in diagnoses but biopsy may be required for histologic characterization. Methods of treatment include surgical resection and irradiation. Corticosteroids are useful in controlling the associated edema. Metastases—from the lung and breast and less often from other sites—are the most common tumors of the cerebellum, especially in adults. The site of the primary tumor may or may not be evident at the time the patient presents with central nervous system involvement. If the site is not evident, careful examination of the
Table 3–12. Tumors of the cerebellum. Percentage of All Cerebellar Tumors
Percentage of Cerebellar Tumors in Adults (≥20 years)
Metastasis
36
56
Astrocytoma
28
10
Medulloblastoma
16
9
Schwannoma
4
7
Hemangioblastoma
4
5
Meningioma
4
5
Ependymoma
2
1
Other
6
7
Type
Data from Gilman S, Bloedel JR, Lechtenberg R: Page 334 in: Disorders of the Cerebellum. Vol 21 of Contemporary Neurology Series. Davis, 1981.
breasts and skin, chest x-ray, urinalysis, and tests for the presence of occult blood in the stool may lead to a diagnosis. The prognosis for patients with cerebellar metastases is usually worse than for patients with supratentorial lesions. Patients with carcinoma of the breast tend to survive longer than those with primary lung tumors. Cerebellar astrocytomas usually occur between the ages of 2 and 20 years, but older patients can also be affected. These tumors are often histologically benign and cystic in appearance. Symptoms of increased intracranial pressure, including headache and vomiting, typically precede the onset of cerebellar dysfunction by several months. If complete surgical resection is possible, cerebellar astrocytoma is potentially curable. Medulloblastoma is common in children but rare in adults. It is believed to originate from neuroectodermal rather than glial cells. In contrast to astrocytomas, medulloblastomas tend to be highly malignant. They often spread through the subarachnoid space and ventricles and may metastasize outside the nervous system. Whereas most childhood medulloblastomas are located in the midline, adult-onset tumors usually arise laterally. Headache, vomiting, ataxia, and visual deterioration are common presenting symptoms. Hemiataxia is a frequent finding in adults because of the hemispheric location of most tumors. Gait ataxia, papilledema, nystagmus, facial palsy, and neck stiffness are also common. Without treatment, medulloblastoma causes death within a few months after presentation. Treatment with partial surgical resection, decompression, and craniospinal irradiation may prolong survival for years. Developing the tumors in adulthood and being female are favorable prognostic factors. Acoustic neuromas have been discussed previously as a cause of vestibular nerve dysfunction. Growth of these or other less common tumors of the cerebellopontine angle may result in compression of the ipsilateral cerebellar hemisphere, causing hemiataxia in addition to the earlier symptoms of vertigo and hearing loss. These tumors are histologically benign and often fully resectable. Unilateral acoustic neuromas can occur in neurofibromatosis 1 (von Recklinghausen disease), whereas bilateral acoustic neuromas are characteristic of neurofibromatosis 2. These disorders are discussed in more detail in the section on cerebellopontine angle tumors (above). Hemangioblastoma is a rare benign tumor that usually affects adults. It can be an isolated abnormality or a feature of von Hippel-Lindau disease. In the latter case, associated features include retinal hemangioblastoma; cysts of the kidney, pancreas, or other viscera; and polycythemia. Patients typically present with headache, and common examination findings include papilledema, nystagmus, and ataxia. Treatment is by surgical resection. Meningiomas of the posterior fossa constitute 9% of all meningiomas. They are benign tumors, derived from
DISORDERS OF EQUILIBRIUM / 123 arachnoidal cap cells, and involve the cerebellum indirectly by compression. The locations of posterior fossa meningiomas (in decreasing order of frequency) include the posterior surface of the petrous bone, the tentorium cerebelli, the clivus, the cerebellar convexities, and the foramen magnum. Meningiomas grow slowly and usually present with headache, although tumors of the cerebellopontine angle or clivus may come to attention when they give rise to cranial nerve or brainstem symptoms. Where possible, complete surgical resection is curative. Ependymomas most commonly arise from the walls or choroid plexus of the fourth ventricle. Like medulloblastomas, they are malignant tumors that seed through the ventricular system and usually occur in children. Because of their location they produce early hydrocephalus; cerebellar signs caused by compression are late or minor manifestations. Surgical resection, craniospinal irradiation, and shunting procedures to relieve hydrocephalus may prolong survival, but widespread dissemination of the tumors and postoperative recurrences are common. 12. POSTERIOR FOSSA MALFORMATIONS Developmental anomalies affecting the cerebellum and brainstem may present with vestibular or cerebellar symptoms in adulthood. This occurs most commonly with type I (adult) Arnold-Chiari malformation, which consists of downward displacement of the cerebellar tonsils through the foramen magnum. The clinical manifestations of this malformation are related to cerebellar involvement, obstructive hydrocephalus, brainstem compression, and syringomyelia. Type II Arnold-Chiari malformation is associated with meningomyelocele (protrusion of the spinal cord, nerve roots, and meninges through a fusion defect in the vertebral column) and has its onset in childhood. Cerebellar ataxia in the type I malformation usually affects the gait and is bilateral; in some cases it is asymmetric. Hydrocephalus leads to headache and vomiting. Dorsal root Posterior column
Vitamin B12 deficiency (subacute combined degeneration)
Table 3–13. Causes of sensory ataxia. Polyneuropathy1 Autosomal dominant sensory ataxic neuropathy Cisplatin (cis-platinum) Dejerine-Sottas disease (HMSN2 type III) Diabetes Diphtheria Hypothyroidism Immune-mediated neuropathies (GALOP syndrome, antiMAG antibody syndrome, Miller Fisher syndrome, antiGD1b antibody syndrome) Isoniazid Paraneoplastic sensory neuronopathy (anti-Hu antibodies) Pyridoxine Refsum disease Taxol Myelopathy3 Acute transverse myelitis AIDS (vacuolar myelopathy) Multiple sclerosis Tumor or cord compression Vascular malformations Polyneuropathy or myelopathy Friedreich ataxia Neurosyphilis (tabes dorsalis) Nitrous oxide Vitamin B12 deficiency Vitamin E deficiency 1 Involving large, myelinated sensory fibers. 2 Hereditary motor and sensory neuropathy. 3 Involving posterior columns.
Compression of the brainstem by herniated cerebellar tissue may be associated with vertigo, nystagmus, and lower cranial nerve palsies. Syringomyelia typically pro-
Dorsal spinocerebellar tract Lateral corticospinal tract
Tabes dorsalis
Friedreich ataxia
Figure 3–16. Principal sites of spinal cord disease (shading) in disorders producing sensory ataxia.
124 / CHAPTER 3 duces a capelike distribution of defective pain and temperature sensation. Arnold-Chiari malformation can be diagnosed by CT or MRI studies that demonstrate cerebellar tonsillar herniation. High cervical laminectomy with decompression of the posterior fossa may be of therapeutic benefit.
SENSORY ATAXIAS Sensory ataxia results from impaired proprioceptive sensation at the level of peripheral nerves or roots, posterior columns of the spinal cord, or sensory pathways in the brain. Clinical findings include defective joint position and vibration sense in the legs and sometimes the arms, unstable stance with Romberg sign, and a gait of slapping or steppage quality. Sensory ataxia can be produced by polyneuropathies that prominently affect large, myelinated sensory fibers (Table 3–13) and by myelopathies, including those resulting from Friedreich ataxia, neurosyphilis (tabes dorsalis), or vitamin B12 deficiency (Figure 3–16). Polyneuropathies, tabes dorsalis, and vitamin B12 deficiency are discussed in detail in Chapter 6.
Gutmann DH et al: The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51–57. Hendley JO. Clinical practice. Otitis media. N Engl J Med 2002;347:1169–1174. Hotson JR, Baloh RW: Acute vestibular syndrome. N Engl J Med 1998;339:680–686. Lockwood AH et al: Tinnitus. N Engl J Med 2002;347:904–910. Nadol FB: Hearing loss. N Engl J Med 1993;329:1092–1102. Parnes LS et al: Diagnosis and management of benign paroxysmal positional vertigo (BPPV). CMAJ 2003;169:681–693. Radtke A et al: Migraine and Ménière’s disease: is there a link? Neurology 2002;59:1700–1704. Zamani AA: Cerebellopontine angle tumors: role of magnetic resonance imaging. Top Magn Reson Imaging 2000;11:98–107.
Cerebellar & central vestibular disorders
Furman JM, Jacob RG: Psychiatric dizziness. Neurology 1997;48:1161–1166. Hain TC, Uddin M: Pharmacological treatment of vertigo. CNS Drugs 2003;17:85–100. Manni E, Petrosini L: A century of cerebellar somatotopy: a debated representation. Nat Rev Neurosci 2004;5:241-249.
Albin RL: Dominant ataxias and Friedreich ataxia: an update. Curr Opin Neurol 2003;16:507–514. Darnell RB, Posner JB: Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543-1554. Dürr A et al: Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med 1996;335:1169–1175. Evidente VG et al: Hereditary ataxias. Mayo Clin Proc 2000;75: 475–490. Jen J et al: Clinical spectrum of episodic ataxia type 2. Neurology 2004;62:17–22. Lynch DR et al: Friedreich ataxia: effects of genetic understanding on clinical evaluation and therapy. Arch Neurol 2002;59: 743–747. Noseworthy JH et al: Multiple sclerosis. N Engl J Med 2000;343: 938–952. Rudick RA et al: Management of multiple sclerosis. N Engl J Med 1997;337:1604–1611. Spacey SD, Gatti RA, Bebb G: The molecular basis and clinical management of ataxia telangiectasia. Can J Neurol Sci 2000;27:184–191.
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Sensory Ataxias
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REFERENCES General
4
Disturbances of Vision
CONTENTS Approach to diagnosis, 125 Functional anatomy of the visual system, 126 Functional anatomy of the ocular motor system, 127 History, 130 Neuroophthalmologic examination, 131
Disorders of the visual system, 144 Monocular disorders, 144 Binocular disorders, 145 Disorders of ocular motility, 146 Gaze palsy, 146 Internuclear ophthalmoplegia, 147 Oculomotor (III) nerve lesions, 148
Trochlear (IV) nerve lesions, 148 Abducens (VI) nerve lesions, 148 Diabetic ophthalmoplegias, 150 Painful ophthalmoplegias, 150 Myasthenia gravis, 150 Ocular myopathies, 150
KEY CONCEPTS Examination of the visual system should be part of even the briefest neurologic examination as it tests the function of much of the brainstem and cerebral hemispheres.
Ptosis (drooping of the eyelid) from oculomotor (III) nerve palsy is complete, but ptosis from sympathetic denervation of the eyelid (Horner syndrome) is only partial.
Test extraocular muscle function (eye movements) in the direction of action of the individual muscles.
Transient monocular blindness is associated with an increased risk of subsequent stroke.
In assessing a swollen optic disk, papilledema (a sign of increased intracranial pressure) is bilateral and painless, whereas papillitis (a sign of optic nerve inflammation, as in multiple sclerosis) is unilateral and painful.
Gaze preference is directed toward the lesion (and away from the hemiparesis) when caused by a hemispheric lesion, but away from the lesion (and toward the hemiparesis) when caused by a brainstem lesion.
Because the anatomic pathways of the visual and ocular motor systems traverse major portions of the brainstem and cerebral hemispheres, neuroophthalmologic signs are often of great value in the anatomic localization of neurologic disease, which in turn suggests possible etiologies. Symptoms most commonly involve vision (disorders of visual
APPROACH TO DIAGNOSIS Disorders that affect the ocular muscles, cranial nerves, or visual or ocular motor pathways in the brain produce a wide variety of neuroophthalmologic disturbances. 125
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126 / CHAPTER 4 pathways) or eye movements (disorders of ocular motility) or both.
FUNCTIONAL ANATOMY OF THE VISUAL SYSTEM Reception of Visual Information
Posterior
Optic chiasm
Visual information enters the nervous system when light, refracted and focused by the lens, creates a visual image on the retina at the posterior pole of the eye (Figure 4–1). The action of the lens causes this image to be reversed in the horizontal and vertical planes. Thus, the superior portion of the visual image falls on the inferior retina and vice versa, and the temporal (lateral) and nasal (medial) fields are likewise reversed (Figure 4–2). The center of the visual field is focused at the fovea, where the retina’s perceptual sensitivity is greatest. Within the retina, photoreceptor cells (rods and Point of fixation
Physiologic blind spot
Temporal retina
Optic nerve Anterior
Retina
ST
SN Visual fields
IT
IN
Figure 4–2. Representation of the visual field at the
18° Temporal visual field
Optic tract
Nasal visual field
13°
Nasal retina
level of the optic nerve, chiasm, and tract. Quadrants of the visual field are designated ST (superior temporal), IT (inferior temporal), SN (superior nasal), and IN (inferior nasal).
cones) transduce incident light into neuronal impulses, which are transmitted by retinal neurons to the optic (II) nerve. At this and all other levels of the visual system, the topographic relations of the visual field are preserved.
Peripheral Visual Pathways
Fovea Optic disk Optic nerve
Figure 4–1. Representation of the visual field at the level of the retina.The point of fixation is focused on the fovea, the physiologic blind spot on the optic disk, the temporal half of the visual field on the nasal side of the retina, and the nasal half of the visual field on the temporal side of the retina.
Each optic nerve contains fibers from one eye, but as shown in Figure 4–2, the nasal (medial) fibers, conveying information from the temporal (lateral) visual fields, cross in the optic chiasm. As a result, each optic tract contains fibers not from one eye but from one half of the visual field. Because of this arrangement, prechiasmal lesions affect vision in the ipsilateral eye and retrochiasmal lesions produce defects in the contralateral half of the visual field of both eyes.
Central Visual Pathways The optic tracts terminate in the lateral geniculate nuclei, where their neurons synapse on neurons that project through the optic radiations to the primary visual or calcarine cortex (area 17), located near the posterior poles of the occipital lobes, and visual association areas (areas 18 and 19). Here, too, the visual image is represented in such a way that its topographic organization
DISTURBANCES OF VISION / 127 is preserved (Figure 4–3). The central region of the visual field (macula) projects to the most posterior portion of the visual cortex, while the inferior and superior parts of the field are represented above and below the calcarine fissure, respectively.
Vascular Supply The vascular supply of the visual system is derived from the ophthalmic, middle cerebral, and posterior cerebral arteries (Figure 4–4); thus, ischemia or infarction in the territory of any of these vessels can produce visual field defects. A. RETINA The retina is supplied by the central retinal artery, a branch of the ophthalmic artery that, in turn, branches from the internal carotid artery. Because the central retinal artery subsequently divides into superior and inferior retinal branches, vascular disease of the retina tends to produce altitudinal (ie, superior or inferior) visual field deficits. B. OPTIC NERVE The optic nerve receives arterial blood primarily from the ophthalmic artery and its branches.
C. OPTIC RADIATIONS As the optic radiations course backward toward the visual cortex, they are supplied by branches of the middle cerebral artery. Ischemia or infarction in the distribution of the middle cerebral artery may thus cause loss of vision in the contralateral visual field. D. PRIMARY VISUAL CORTEX The principal source of arterial blood for the primary visual cortex is the posterior cerebral artery. Occlusion of one posterior cerebral artery produces blindness in the contralateral visual field, although the dual (middle and posterior cerebral) arterial supply to the macular region of the visual cortex (Figures 4–3 and 4–4) may spare central (macular) vision. Because the posterior cerebral arteries arise together from the basilar artery, occlusion at the tip of the basilar artery can cause bilateral occipital infarction and complete cortical blindness—although, in some cases, macular vision is spared.
FUNCTIONAL ANATOMY OF THE OCULAR MOTOR SYSTEM Extraocular Muscles Movement of the eyes is accomplished by the action of six muscles attached to each globe (Figure 4–5A). These muscles act to move the eye into each of six cardinal positions of gaze (Figure 4–5B and C). Equal and opposed actions of these six muscles in the resting state place the eye in mid or primary position, ie, looking directly forward. When the function of one extraocular muscle is disrupted, the eye is unable to move in the direction of action of the affected muscle (ophthalmoplegia) and may deviate in the opposite direction because of the unopposed action of other extraocular muscles. When the eyes are thus misaligned, visual images of perceived objects fall on a different region of each retina, creating the illusion of double vision, or diplopia.
Cranial Nerves Upper peripheral quadrant of retina Upper quadrant of macula Lower quadrant of macula Lower peripheral quadrant of retina
Figure 4–3. Representation of the visual field at the level of the primary visual cortex, midsagittal view, shows the medial surface of the right occipital lobe, which receives visual input from the left side of the visual field of both eyes.
The extraocular muscles are innervated by the oculomotor (III), trochlear (IV), and abducens (VI) nerves. Because of this differential innervation of the ocular muscles, the pattern of their involvement in pathologic conditions can help to distinguish a disorder of the ocular muscles per se from a disorder that affects a cranial nerve. Cranial nerves that control eye movement traverse long distances to pass from the brainstem to the eye; they are thereby rendered vulnerable to injury by a variety of pathologic processes. A. NERVE III The oculomotor nerve supplies the medial rectus, superior and inferior rectus, and inferior oblique muscles
128 / CHAPTER 4
Optic nerve
Left eye
Ciliary arteries Central retinal artery Ophthalmic artery Optic chiasm Internal carotid artery
Middle cerebral artery
Optic tract
Anterior choroidal artery
Basilar artery Posterior cerebral artery Lateral geniculate body
Optic radiations
Deep branch of middle cerebral artery
Occipital cortex
Figure 4–4. Arterial supply of the visual system, viewed from below. and carries fibers to the levator palpebrae (which raises the eyelid). It also supplies the parasympathetic fibers responsible for pupillary constriction. With a complete nerve III lesion, the eye is partially abducted and there is an inability to adduct, elevate, and depress the eye; the eyelid droops (ptosis), and the pupil is nonreactive. B. NERVE IV The trochlear nerve innervates the superior oblique muscle. Lesions of this nerve result in defective depression of the adducted eye. C. NERVE VI Lesions of the abducens nerve cause l
